Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament

ABSTRACT

The invention relates to spirocyclically substituted 1,3-propane dioxide derivatives, and to the physiologically compatible salts thereof. 
     The invention relates to compounds of the formula I 
                         
in which R1, R2, R3, R4, R5, R6, R7, R8, A and X are each defined as specified, and the physiologically compatible salts thereof. The compounds are suitable, for example, for treatment of diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/422,799 filed on Dec. 14, 2010.

The invention relates to spirocyclically substituted 1,3-propane dioxidederivatives, and to the physiologically compatible salts thereof.

Structurally similar compounds have already been described in the priorart (see WO00/84888), as has the use thereof as PPAR agonists orantagonists.

It was an object of the invention to provide compounds which display atherapeutically utilizable action. It was a further object to find novelcompounds suitable for treatment of hyperglycemia and of diabetes. Itwas a further object to find novel compounds which activate the GPR40receptor and are thus suitable for treatment of hyperglycemia and ofdiabetes.

The invention therefore relates to compounds of the formula I

in which

-   R1 is O—(C₁-C₆)-alkyl, (C₂-C₆)-alkynyl,    (C₂-C₆)-alkynylene-(C₃-C₁₀)-cycloalkyl, where the O—(C₁-C₆)-alkyl    radical, the (C₂-C₆)-alkynyl radical and the    (C₂-C₆)-alkynylene-(C₃-C₁₀)-cycloalkyl radical may be mono- or    polysubstituted by fluorine;-   R2, R6 are each independently H, F, Cl, Br, CN, (C₁-C₆)-alkyl,    O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, where the (C₁-C₆)-alkyl radical,    O—(C₁-C₆)-alkyl radical and the CO—(C₁-C₆)-alkyl radical may be    mono- or polysubstituted by fluorine;-   R3, R4, R5 are each independently H, F, Cl, Br, I, NO₂, CN,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl,    NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,    SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,    CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₆-C₁₀)-aryl,    (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered heterocycle, where the    (C₁-C₆)-alkyl radical, the O—(C₁-C₆)-alkyl radical, the    (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl radical, the NH(C₁-C₆)-alkyl    radical, the N((C₁-C₆)-alkyl)₂ radical, the SO₂—CH₃ radical, the    SO₂—NH(C₁-C₆)-alkyl radical, SO₂—N((C₁-C₆)-alkyl)₂ radical,    COO—(C₁-C₆)-alkyl radical, the CONH(C₁-C₆)-alkyl radical and the    CON((C₁-C₆)-alkyl)₂ radical may each be mono- or polysubstituted by    F, and where the (C₆-C₁₀)-aryl radical, the (C₃-C₁₀)-cycloalkyl    radical and the 4- to 12-membered heterocycle radical may each be    mono- to trisubstituted by    -   F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂,        O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,        N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,        SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,        CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂ or SF₅;-   R7, R8 are each independently H, F;-   A is (C₆-C₁₀)-aryl, (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered    heterocycle;-   X is —CH₂—, —CH₂—CH₂—, —CH₂O—, —OCH₂—, —CH₂S, —SCH₂—, —CH₂SO—,    —SOCH₂—, —CH₂SO₂—, —SO₂CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 are each independently H, F, Cl, Br, CN, (C₁-C₆)-alkyl,    CO—(C₁-C₆)-alkyl, where the (C₁-C₆)-alkyl radical, O—(C₁-C₆)-alkyl    radical and the CO—(C₁-C₆)-alkyl radical may be mono- or    polysubstituted by fluorine;-   R3, R4, R5 are each independently H, F, Cl, Br, I, NO₂, CN,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl,    NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,    SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,    CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₆-C₁₀)-aryl,    (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered heterocycle, where the    (C₁-C₆)-alkyl radical, the O—(C₁-C₆)-alkyl radical, the    (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl radical, the NH(C₁-C₆)-alkyl    radical, the N((C₁-C₆)-alkyl)₂ radical, the SO₂—CH₃ radical, the    SO₂—NH(C₁-C₆)-alkyl radical, SO₂—N((C₁-C₆)-alkyl)₂ radical,    COO—(C₁-C₆)-alkyl radical, the CONH(C₁-C₆)-alkyl radical and the    CON((C₁-C₆)-alkyl)₂ radical may each be mono- or polysubstituted by    F, and where the (C₆-C₁₀)-aryl radical, the (C₃-C₁₀)-cycloalkyl    radical and the 4- to 12-membered heterocycle radical may each be    mono- to trisubstituted by    -   F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂,        O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,        N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,        SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,        CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂ or SF₅;-   R7, R8 are each independently H, F;-   A is (C₆-C₁₀)-aryl, (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered    heterocycle;-   X is —CH₂—, —CH₂—CH₂—, —CH₂O—, —OCH₂—, —CH₂S, —SCH₂—, —CH₂SO—,    —SOCH₂—, —CH₂SO₂—, —SO₂CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 are each independently H, F, Cl, Br, CN, (C₁-C₆)-alkyl,    O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, where the (C₁-C₆)-alkyl radical,    O—(C₁-C₆)-alkyl radical and the CO—(C₁-C₆)-alkyl radical may be    mono- or polysubstituted by fluorine;-   R3, R4, R5 are each independently H, F, Cl, Br, I, NO₂, CN,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl,    NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,    SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,    CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₆-C₁₀)-aryl,    (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered heterocycle, where the    (C₁-C₆)-alkyl radical, the O—(C₁-C₆)-alkyl radical, the    (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl radical, the NH(C₁-C₆)-alkyl    radical, the N((C₁-C₆)-alkyl)₂ radical, the SO₂—O—CH₃ radical, the    SO₂—NH(C₁-C₆)-alkyl radical, SO₂—N((C₁-C₆)-alkyl)₂ radical,    COO—(C₁-C₆)-alkyl radical, the CONH(C₁-C₆)-alkyl radical and the    CON((C₁-C₆)-alkyl)₂ radical may each be mono- or polysubstituted by    F, and where the (C₆-C₁₀)-aryl radical, the (C₃-C₁₀)-cycloalkyl    radical and the 4- to 12-membered heterocycle radical may each be    mono- to trisubstituted by    -   F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂,        O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,        N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,        SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,        CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂ or SF₅;-   R7, R8 are each independently H, F;-   A is phenyl, pyridyl;-   X is —CH₂—, —CH₂—CH₂—, —OCH₂—, —CH₂S, —SCH₂—, —CH₂SO—, —SOCH₂—,    —CH₂SO₂—, —SO₂CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 is H;-   R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃,    (C₁-C₆)-alkyl;-   R5 is H;-   R7, R8 is H;-   A is phenyl, pyridyl;-   X is —CH₂—, —CH₂—CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 is H;-   R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃,    (C₁-C₆)-alkyl;-   R5 is H;-   R7, R8 is H;-   A is phenyl;-   X is —CH₂—, —CH₂—CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 is H;-   R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃,    (C₁-C₆)-alkyl;-   R5 is H;-   R7, R8 is H;-   A is pyridyl;-   X is —CH₂—, —CH₂—CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 is H;-   R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃,    (C₁-C₆)-alkyl;-   R5 is H;-   R7, R8 is H;-   A is phenyl;-   X is —CH₂—;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is (C₂-C₆)-alkynyl;-   R2, R6 is H;-   R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃,    (C₁-C₆)-alkyl;-   R5 is H;-   R7, R8 is H;-   A is pyridyl;-   X is —CH₂—;    and physiologically compatible salts thereof.

If radicals or substituents can occur more than once in the compounds ofthe formula I, they may each independently be defined as specified andbe the same or different.

The alkyl and alkynyl radicals in the R1, R2, R3, R4, R5 and R6 radicalsmay be either straight-chain or branched.

The invention relates to compounds of the formula I in the form of thesalts, racemates, racemic mixtures and pure enantiomers thereof, and ofthe diastereomers and mixtures thereof.

The invention further provides both stereoisomer mixtures of the formulaI and the pure stereoisomers of the formula I, and also diastereomermixtures of the formula I and the pure diastereomers. The mixtures areseparated, for example, by a chromatographic route.

The present invention encompasses all possible tautomeric forms of thecompounds of the formula I.

Owing to their higher water solubility compared to the starting or basecompounds, pharmaceutically acceptable salts are particularly suitablefor medical applications. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the inventive compounds are salts of inorganic acidsand organic acids.

Salts with a pharmaceutically unacceptable anion likewise form part ofthe scope of the invention as useful intermediates for the preparationor purification of pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and the salts andsolvates thereof, as described herein.

An alkyl radical is understood to mean a straight-chain or branchedhydrocarbon chain, for example methyl, ethyl, isopropyl, tert-butyl,hexyl. The alkyl radicals may be mono- or polysubstituted as describedabove.

The invention also encompasses solvates, hydrates and alcohol adducts ofthe compounds of the formula I.

The compound(s) of the formula I may also be administered in combinationwith further active ingredients.

The amount of a compound of the formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, 0.1 ng to 100 mg, typically1 ng to 100 mg, per milliliter. Single doses may contain, for example, 1mg to 10 g of the active ingredient. Thus, ampoules for injections maycontain, for example, from 1 mg to 100 mg, and orally administrablesingle-dose formulations, for example tablets or capsules, may contain,for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. Fortreatment of the abovementioned conditions, the compounds of the formulaI themselves may be used as the compound, but they are preferablypresent with a compatible carrier in the form of a pharmaceuticalcomposition. The carrier must, of course, be acceptable in the sensethat it is compatible with the other ingredients of the composition andis not harmful for the patient's health. The carrier may be a solid or aliquid or both and is preferably formulated with the compound as asingle dose, for example as a tablet, which may contain 0.05% to 95% byweight of the active ingredient. Other pharmaceutically activesubstances may likewise be present, including other compounds of formulaI. The pharmaceutical compositions of the invention can be produced byone of the known pharmaceutical methods, which essentially consist ofmixing the ingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a defined amount of the compound offormula I; as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional ingredients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surfactant(s)/dispersant(s) in a suitable machine. Molded tabletscan be produced by molding the compound, which is in powder form and hasbeen moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise lozenges which contain a compound of formula Iwith a flavoring, typically sucrose, and gum arabic or tragacanth, andpastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain 0.1 to 5% by weight ofthe active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula I with one or more conventionalsolid carriers, for example cocoa butter, and shaping resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. The carriers used may be petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of 0.1 to15% by weight of the composition, for example 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses may be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular option is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further suitable active ingredients for the combination preparationsare:

All antidiabetics mentioned in the Rote Liste 2010, chapter 12; allweight-reducing agents/appetite suppressants mentioned in the Rote Liste2010, chapter 1; all diuretics mentioned in the Rote Liste 2010, chapter36; all lipid-lowering agents mentioned in the Rote Liste 2010, chapter58. They can be combined with the inventive compound of the formula I,especially for a synergistic improvement in action. The activeingredient combination can be administered either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. When the active ingredientsare administered by separate administration of the active ingredients,this can be done simultaneously or successively. Most of the activeingredients mentioned hereinafter are disclosed in the USP Dictionary ofUSAN and International Drug Names, US Pharmacopeia, Rockville 2006.

Antidiabetics include insulin and insulin derivatives, for exampleLantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir),Humalog® (Insulin Lispro), insulin degludec, insulin aspart,polyethylene glycosidized (PEGylated) Insulin Lispro as described inWO2009152128, Humulin®, VIAject™, SuliXen®, VIAject™ or those asdescribed in WO2005005477 (Novo Nordisk), fast-acting insulins (see U.S.Pat. No. 6,221,633), inhalable insulins, for example Exubera®, Nasulin™,or oral insulins, for example IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), or Technosphere® insulin (MannKind) or Cobalamin™ oralinsulin or ORMD-0801 or insulins or insulin precursors as described inWO2007128815, WO2007128817, WO2008034881, WO2008049711, WO2008145721,WO2009034117, WO2009060071, WO2009133099 or insulins which can beadministered transdermally; additionally included are also those insulinderivatives which are bonded to albumin by a bifunctional linker, asdescribed, for example, in WO2009121884;

GLP-1 derivatives and GLP-1 agonists, for example exenatide or specificformulations thereof, as described, for example, in WO2008061355,WO2009080024, WO2009080032, liraglutide, taspoglutide (R-1583),albiglutide, lixisenatide or those which have been disclosed in WO98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A/S,in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen,pramlintide acetate (Symlin; Amylin Pharmaceuticals), inhalable GLP-1(MKC-253 from MannKind) AVE-0010, BIM-51077 (R-1583, ITM-077),PC-DAC:exendin-4 (an exendin-4 analog which is bonded covalently torecombinant human albumin), biotinylated exendin (WO2009107900), aspecific formulation of exendin-4 as described in US2009238879, CVX-73,CVX-98 and CVx-96 (GLP-1 analogs which are bonded covalently to amonoclonal antibody which has specific binding sites for the GLP-1peptide), CNTO-736 (a GLP-1 analog which is bonded to a domain whichincludes the Fc portion of an antibody), PGC-GLP-1 (GLP-1 bonded to ananocarrier), agonists or modulators, as described, for example, in D.Chen et al., Proc. Natl. Acad. Sci, USA 104 (2007) 943, those asdescribed in WO2006124529, WO2007124461, WO2008062457, WO2008082274,WO2008101017, WO2008081418, WO2008112939, WO2008112941, WO2008113601,WO2008116294, WO2008116648, WO2008119238, WO2008148839, US2008299096,WO2008152403, WO2009030738, WO2009030771, WO2009030774, WO2009035540,WO2009058734, WO2009111700, WO2009125424, WO2009129696, WO2009149148,peptides, for example obinepitide (TM-30338), orally active GLP-1analogs (e.g. NN9924 from Novo Nordisk), amylin receptor agonists, asdescribed, for example, in WO2007104789, WO2009034119, analogs of thehuman GLP-1, as described in WO2007120899, WO2008022015, WO2008056726,chimeric pegylated peptides containing both GLP-1 and glucagon residues,as described, for example, in WO2008101017, WO2009155257, WO2009155258,glycosylated GLP-1 derivatives as described in WO2009153960, and orallyactive hypoglycemic ingredients.

Antidiabetics also include gastrin analogs, for example TT-223.

Antidiabetics additionally include poly- or monoclonal antibodiesdirected, for example, against interleukin 1 beta (IL-1β), for exampleXOMA-052.

Antidiabetics additionally include peptides which can bind to the humanpro-islet peptide (HIP) receptor, as described, for example, inWO2009049222.

Antidiabetics also include agonists of the glucose-dependentinsulinotropic polypeptide (GIP) receptor, as described, for example, inWO2006121860.

Antidiabetics also include the glucose-dependent insulinotropicpolypeptide (GIP), and also analogous compounds, as described, forexample, in WO2008021560, WO2010016935, WO2010016936, WO2010016938,WO2010016940, WO2010016944.

Additionally included are analogs and theivatives of human pancreaticpolypeptide, as described, for example, in WO2009007714.

Antidiabetics additionally include encapsulated insulin-producingporcine cells, for example DiabeCell®.

Antidiabetics also include analogs and theivatives of fibroblast growthfactor 21 (FGF-21), as described, for example, in WO2009149171,WO2010006214.

The orally active hypoglycemic ingredients preferably includesulfonylureas,

biguanidines,

meglitinides,

oxadiazolidinediones,

thiazolidinediones,

PPAR and RXR modulators,

glucosidase inhibitors,

inhibitors of glycogen phosphorylase,

glucagon receptor antagonists,

glucokinase activators,

inhibitors of fructose 1,6-bisphosphatase,

modulators of glucose transporter 4 (GLUT4),

inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT),

GLP-1 agonists,

potassium channel openers, for example pinacidil, cromakalim, diazoxide,diazoxide choline salt, or those as described in R. D. Can et al.,Diabetes 52, 2003, 2513.2518, in J. B. Hansen et al., Current MedicinalChemistry 11, 2004, 1595-1615, in T. M. Tagmose et al., J. Med. Chem.47, 2004, 3202-3211 or in M. J. Coghlan et al., J. Med. Chem. 44, 2001,1627-1653, or those which have been disclosed in WO 97/26265 and WO99/03861 by Novo Nordisk A/S, active ingredients which act on theATP-dependent potassium channel of the beta cells,inhibitors of dipeptidyl peptidase-IV (DPP-IV),insulin sensitizers,inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,modulators of glucose uptake, of glucose transport and of glucosereabsorption,modulators of sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1),inhibitors of protein tyrosine phosphatase-1B (PTP-1B),nicotinic acid receptor agonists,inhibitors of hormone-sensitive or endothelial lipases,inhibitors of acetyl-CoA carboxylase (ACC1 and/or ACC2) orinhibitors of GSK-3 beta.

Also included are compounds which modify the lipid metabolism, such asactive antihyperlipidemic ingredients and active antilipidemicingredients,

HMG-CoA reductase inhibitors,

farnesoid X receptor (FXR) modulators,

fibrates,

cholesterol reabsorption inhibitors,

CETP inhibitors,

bile acid absorption inhibitors,

MTP inhibitors,

estrogen receptor gamma agonists (ERR γ agonists),

sigma-1 receptor antagonists,

antagonists of the somatostatin 5 receptor (SSTS receptor);

compounds which reduce food intake, and

compounds which increase thermogenesis.

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an insulin sensitizer, for examplePN-2034 or ISIS-113715.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, for example sulfonylureas, forexample tolbutamide, glibenclamide, glipizide, gliclazide orglimepiride, or those formulations as described, for example, inEP2103302.

In one embodiment, the compound of the formula I is administered incombination with a tablet which comprises both glimepiride, which isreleased rapidly, and metformin, which is released over a longer period(as described, for example, in US2007264331, WO2008050987,WO2008062273).

In one embodiment, the compound of the formula I is administered incombination with a biguanide, for example metformin or one of its salts.

In a further embodiment, the compound of the formula I is administeredin combination with a guanidine, for example benzylguanidine or one ofits salts, or those guanidines as described in WO2009087395.

In another embodiment, the compound of the formula I is administered incombination with a meglitinide, for example repaglinide, nateglinide ormitiglinide.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with a glitazone, e.g. pioglitazonehydrochloride.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with an alpha-glucosidase inhibitor.

In a further embodiment, the compound of the formula I is administeredin combination with antidiabetic compounds, as described inWO2007095462, WO2007101060, WO2007105650.

In a further embodiment, the compound of the formula I is administeredin combination with antihypoglycemic compounds, as described inWO2007137008, WO2008020607.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione, for example troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 by Dr. Reddy's Research Foundation, especially5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist, for examplerosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-011(rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384,or those as described in WO2005086904, WO2007060992, WO2007100027,WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969,WO2008010238, WO2008017398, WO2008028188, WO2008066356, WO2008084303,WO2008089461-WO2008089464, WO2008093639, WO2008096769, WO2008096820,WO2008096829, US2008194617, WO2008099944, WO2008108602, WO2008109334,WO2008110062, WO2008126731, WO2008126732, WO2008137105, WO2009005672,WO2009038681, WO2009046606, WO2009080821, WO2009083526, WO2009102226,WO2009128558, WO2009139340.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a solid combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Tandemact™, a solid combination ofpioglitazone with glimepiride.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of pioglitazonehydrochloride with an angiotensin II agonist, for example TAK-536.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist or mixed PPARalpha/PPAR delta agonist, for example GW9578, GW-590735, K-111, LY-674,KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939, orthose as described in WO2001040207, WO2002096894, WO2005097076,WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515,WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043,WO2008006043, WO2008006044, WO2008012470, WO2008035359, WO2008087365,WO2008087366, WO2008087367, WO2008117982, JP2009023975, WO2009033561,WO2009047240, WO2009072581, WO2009080248, WO2009080242, WO2009149819,WO2009149820, WO2009147121, WO2009153496, WO2010008299, WO2010014771.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist, forexample naveglitazar, aleglitazar, LY-510929, ONO-5129, E-3030, AVE8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate), MBX-213,KY-201, BMS-759509, or as described in WO 00/64888, WO 00/64876,WO03/020269, WO2004024726, WO2007099553, US2007276041, WO2007085135,WO2007085136, WO2007141423, WO2008016175, WO2008053331, WO2008109697,WO2008109700, WO2008108735, WO2009026657, WO2009026658, WO2009149819,WO2009149820 or in J. P. Berger et al., TRENDS in PharmacologicalSciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist, for exampleGW-501516, or as described in WO2006059744, WO2006084176, WO2006029699,WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094,WO2007119887, WO2007141423, US2008004281, WO2008016175, WO2008066356,WO2008071311, WO2008084962, US2008176861, WO2009012650, US2009137671,WO2009080223, WO2009149819, WO2009149820, WO2010000353.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a pan-SPPARM (selective PPAR modulatoralpha, gamma, delta), for example GFT-505, indeglitazar, or those asdescribed in WO2008035359, WO2009072581.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPARgamma agonists/antagonists.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor, for example miglitol oracarbose, or those as described, for example, in WO2007114532,WO2007140230, US2007287674, US2008103201, WO2008065796, WO2008082017,US2009076129.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, for examplePSN-357 or FR-258900, or those as described in WO2003084922,WO2004007455, WO2005073229-31, WO2005067932, WO2008062739, WO2008099000,WO2008113760, WO2009016118, WO2009016119, WO2009030715, WO2009045830,WO2009045831, WO2009127723.

In another embodiment, the compound of the formula I is administered incombination with an inhibitor of the interaction of liver glycogenphosphorylase with the protein PPP1R3 (GL subunit of glycogen-associatedprotein phosphatase 1 (PP1)), as described, for example, inWO2009030715.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists, for example A-770077 orNNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488,WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284,WO2007123581, WO2007136577, WO2008042223, WO2008098244, WO2009057784,WO2009058662, WO2009058734, WO2009110520, WO2009120530, WO2009140342,WO2010019828.

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-325568, whichinhibits the production of the glucagon receptor.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, for example LY-2121260(WO2004063179), PSN-105, PSN-110, GKA-50, or those as described, forexample, in WO2004072031, WO2004072066, WO2005080360, WO2005044801,WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549,WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61,WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365,WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846,WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847,WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103,WO2007125105, US2007281942, WO2008005914, WO2008005964, WO2008043701,WO2008044777, WO2008047821, US2008096877, WO2008050117, WO2008050101,WO2008059625, US2008146625, WO2008078674, WO2008079787, WO2008084043,WO2008084044, WO2008084872, WO2008089892, WO2008091770, WO2008075073,WO2008084043, WO2008084044, WO2008084872, WO2008084873, WO2008089892,WO2008091770, JP2008189659, WO2008104994, WO2008111473, WO2008116107,WO2008118718, WO2008120754, US2008280875, WO2008136428, WO2008136444,WO2008149382, WO2008154563, WO2008156174, WO2008156757, US2009030046,WO2009018065, WO2009023718, WO2009039944, WO2009042435, WO2009046784,WO2009046802, WO2009047798, WO2009063821, WO2009081782, WO2009082152,WO2009083553, WO2009091014, US2009181981, WO2009092432, WO2009099080,WO2009106203, WO2009106209, WO2009109270, WO2009125873, WO2009127544,WO2009127546, WO2009128481, WO2009133687, WO2009140624, WO2010013161,WO2010015849, WO2010018800.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, as described, forexample, in FR-225654, WO2008053446.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose 1,6-bisphosphatase (FBPase), forexample MB-07729, CS-917 (MB-06322) or MB-07803, or those as describedin WO2006023515, WO2006104030, WO2007014619, WO2007137962, WO2008019309,WO2008037628, WO2009012039, EP2058308, WO2009068467, WO2009068468.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), forexample KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12),835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine:fructose-6-phosphateamidotransferase (GFAT), as described, for example, in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), forexample vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptinphosphate, saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200 (melogliptin), GW-825964X, KRP-104,DP-893, ABT-341, ABT-279 or another salt thereof, S-40010, S-40755,PF-00734200, BI-1356, PHX-1149, DSP-7238, alogliptin benzoate,linagliptin, melogliptin, carmegliptin, or those compounds as describedin WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828,WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064,WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117,WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826,WO2006078676, WO2006073167, WO2006068163, WO2006085685, WO2006090915,WO2006104356, WO2006127530, WO2006111261, US2006890898, US2006803357,US2006303661, WO2007015767 (LY-2463665), WO2007024993, WO2007029086,WO2007063928, WO2007070434, WO2007071738, WO2007071576, WO2007077508,WO2007087231, WO2007097931, WO2007099385, WO2007100374, WO2007112347,WO2007112669, WO2007113226, WO2007113634, WO2007115821, WO2007116092,US2007259900, EP1852108, US2007270492, WO2007126745, WO2007136603,WO2007142253, WO2007148185, WO2008017670, US2008051452, WO2008027273,WO2008028662, WO2008029217, JP2008031064, JP2008063256, WO2008033851,WO2008040974, WO2008040995, WO2008060488, WO2008064107, WO2008066070,WO2008077597, JP2008156318, WO2008087560, WO2008089636, WO2008093960,WO2008096841, WO2008101953, WO2008118848, WO2008119005, WO2008119208,WO2008120813, WO2008121506, WO2008130151, WO2008131149, WO2009003681,WO2009014676, WO2009025784, WO2009027276, WO2009037719, WO2009068531,WO2009070314, WO2009065298, WO2009082134, WO2009082881, WO2009084497,WO2009093269, WO2009099171, WO2009099172, WO2009111239, WO2009113423,WO2009116067, US2009247532, WO2010000469, WO2010015664.

In one embodiment, the compound of the formula I is administered incombination with Janumet™, a solid combination of sitagliptin phosphatewith metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with Eucreas®, a solid combination of vildagliptin withmetformin hydrochloride.

In a further embodiment, the compound of the formula I is administeredin combination with a solid combination of alogliptin benzoate withpioglitazone.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of a salt of sitagliptin withmetformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with omega-3 fattyacids or omega-3 fatty acid esters, as described, for example, inWO2007128801.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with metforminhydrochloride, as described, for example, in WO2009121945.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with a GPR-119agonist, as described, for example, in WO2009123992.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with miglitol, asdescribed, for example, in WO2009139362.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of a salt of sitagliptin withmetformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of alopliptin benzoate withpioglitazone hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, forexample KCP-265 (WO2003097064), or those as described in WO2007026761,WO2008045484, US2008194617, WO2009109259, WO2009109341.

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR), for example APD-668.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor, forexample SB-204990.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 and/or 2 (SGLT1, SGLT2), for example KGA-2727, T-1095, SGL-0010, AVE2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin,dapagliflozin or remogliflozin etabonate, canagliflozin, or asdescribed, for example, in WO2004007517, WO200452903, WO200452902,PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161,WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197,WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895,WO2007080170, WO2007093610, WO2007126117, WO2007128480, WO2007129668,US2007275907, WO2007136116, WO2007143316, WO2007147478, WO2008001864,WO2008002824, WO2008013277, WO2008013280, WO2008013321, WO2008013322,WO2008016132, WO2008020011, JP2008031161, WO2008034859, WO2008042688,WO2008044762, WO2008046497, WO2008049923, WO2008055870, WO2008055940,WO2008069327, WO2008070609, WO2008071288, WO2008072726, WO2008083200,WO2008090209, WO2008090210, WO2008101586, WO2008101939, WO2008116179,WO2008116195, US2008242596, US2008287529, WO2009026537, WO2009049731,WO2009076550, WO2009084531, WO2009096503, WO2009100936, WO2009121939,WO2009124638, WO2009128421, WO2009135673, WO2010009197, WO2010018435,WO2010018438 or by A. L. Handlon in Expert Opin. Ther. Patents (2005)15(11), 1531-1540.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of an SGLTinhibitor with a DPP-IV inhibitor, as described in WO2009091082.

In one embodiment, the compound of the formula I is administered incombination with a stimulator of glucose transport, as described, forexample, in WO2008136392, WO2008136393.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), for example BVT-2733, JNJ-25918646, INCB-13739, INCB-20817,DIO-92 ((−)-ketoconazole) or those as described, for example, inWO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009,WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983,WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427,WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351,WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877,WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173,WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750,WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329,WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436,WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508,WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584,WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768,WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150,WO2007092435, WO2007089683, WO2007101270, WO2007105753, WO2007107470,WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935,WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254,WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763,WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898,WO2007135427, WO2007139992, WO2007144394, WO2007145834. WO2007145835,WO2007146761, WO2008000950, WO2008000951, WO2008003611, WO2008005910,WO2008006702, WO2008006703, WO2008011453, WO2008012532, WO2008024497,WO2008024892, WO2008032164, WO2008034032, WO2008043544, WO2008044656,WO2008046758, WO2008052638, WO2008053194, WO2008071169, WO2008074384,WO2008076336, WO2008076862, WO2008078725, WO2008087654, WO2008088540,WO2008099145, WO2008101885, WO2008101886, WO2008101907, WO2008101914,WO2008106128, WO2008110196, WO2008119017, WO2008120655, WO2008127924,WO2008130951, WO2008134221, WO2008142859, WO2008142986, WO2008157752,WO2009001817, WO2009010416, WO2009017664, WO2009020140, WO2009023180,WO2009023181, WO2009023664, WO2009026422, WO2009038064, WO2009045753,WO2009056881, WO2009059666, WO2009061498, WO2009063061, WO2009070497,WO2009074789, WO2009075835, WO2009088997, WO2009090239, WO2009094169,WO2009098501, WO2009100872, WO2009102428, WO2009102460, WO2009102761,WO2009106817, WO2009108332, WO2009112691, WO2009112845, WO2009114173,WO2009117109, US2009264401, WO2009118473, WO2009131669, WO2009132986,WO2009134384, WO2009134387, WO2009134392, WO2009134400, WO2009135581,WO2009138386, WO2010006940, WO2010010157, WO2010010174, WO2010011917.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase-1B (PTP-1B),as described, for example, in WO200119830-31, WO200117516, WO2004506446,WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755,WO2007115058, US2008004325, WO2008033455, WO2008033931, WO2008033932,WO2008033934, WO2008089581, WO2008148744, WO2009032321, WO2009109999,WO2009109998.

In a further embodiment, the compound of the formula I is administeredin combination with stimulators of tyrosine kinase B (Trk-B), asdescribed, for example, in WO2010014613.

In a further embodiment, the compound of the formula I is administeredin combination with beta 3 agonists (also called beta-3 adrenoceptoragonists), as described, for example, in Physiol. Behav. 2004 Sep. 15;82(2-3):489-96, J Clin Invest (1998) 101: 2387-93, Curr. Pharma. Des.2001 September; 7(14):1433-49, Bioorganic & Medicinal Chemistry Lettersvolume 14, number 13, Jul. 5, 2004, pages 3525-3529 (BMS-201620).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonists; NAR agonists (nicotinic acid receptor agonists)), for examplenicotinic acid or extended release niacin in conjunction with MK-0524A(laropiprant) or MK-0524, or those compounds as described inWO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108,WO2006085112, WO2006085113, WO2006124490, WO2006113150, WO2007002557,WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532,WO2007092364, WO2007120575, WO2007134986, WO2007150025, WO2007150026,WO2008016968, WO2008051403, WO2008086949, WO2008091338, WO2008097535,WO2008099448, US2008234277, WO2008127591.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of niacin withsimvastatin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant).

In a further embodiment of the invention, the compound of the formula Iis administered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant) and with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with nicotinic acid or another nicotinicacid receptor agonist and a prostaglandin DP receptor antagonist, forexample those as described in WO2008039882.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of niacin withmeloxicam, as described, for example, in WO2009149056.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116, as described, forexample, in WO2006067531, WO2006067532.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR40, as described, for example, inWO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225,WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622,WO2007136572, WO2008001931, WO2008030520, WO2008030618, WO2008054674,WO2008054675, WO2008066097, US2008176912, WO2008130514, WO2009038204,WO2009039942, WO2009039943, WO2009048527, WO2009054479, WO2009058237,WO2009111056, WO2010012650.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 (G-protein-coupledglucose-dependent insulinotropic receptor), for example PSN-119-1,PSN-821, PSN-119-2, MBX-2982 or those as described, for example, inWO2004065380, WO2005061489 (PSN-632408), WO2006083491, WO2007003960-62and WO2007003964, WO2007035355, WO2007116229, WO2007116230,WO2008005569, WO2008005576, WO2008008887, WO2008008895, WO2008025798,WO2008025799, WO2008025800, WO2008070692, WO2008076243, WO200807692,WO2008081204, WO2008081205, WO2008081206, WO2008081207, WO2008081208,WO2008083238, WO2008085316, WO2008109702, WO2008130581, WO2008130584,WO2008130615, WO2008137435, WO2008137436, WO2009012275, WO2009012277,WO2009014910, WO2009034388, WO2009038974, WO2009050522, WO2009050523,WO2009055331, WO2009105715, WO2009105717, WO2009105722, WO2009106561,WO2009106565, WO2009117421, WO2009125434, WO2009126535, WO2009129036,US2009286812, WO2009143049, WO2009150144, WO2010001166, WO2010004343,WO2010004344, WO2010004345, WO2010004346, WO2010004347, WO2010004348,WO2010008739, WO2010006191, WO2010009183, WO2010009195, WO2010009207,WO2010009208, WO2010014593.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of GPR120, as described, for example, inEP1688138, WO2008066131, WO2008066131, WO2008103500, WO2008103501,WO2008139879, WO2009038204, WO2009147990, WO2010008831.

In another embodiment, the compound of the formula I is administered incombination with antagonists of GPR105, as described, for example, inWO2009000087, WO2009070873.

In a further embodiment, the compound of the formula I is administeredin combination with agonists of GPR43, for example ESN-282.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) and/orphospholipases, as described, for example, in WO2005073199,WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837,WO2008122352, WO2008122357, WO2009009287.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of endothelial lipase, as described, forexample, in WO2007110216.

In one embodiment, the compound of the formula I is administered incombination with a phospholipase A2 inhibitor, for example darapladib orA-002, or those as described in WO2008048866, WO20080488867,US2009062369.

In one embodiment, the compound of the formula I is administered incombination with myricitrin, a lipase inhibitor (WO2007119827).

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta), as described, for example, in US2005222220, WO2005085230,WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908,US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343,EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117,WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109,WO2007125110, US2007281949, WO2008002244, WO2008002245, WO2008016123,WO2008023239, WO2008044700, WO2008056266, WO2008057940, WO2008077138,EP1939191, EP1939192, WO2008078196, WO2008094992, WO2008112642,WO2008112651, WO2008113469, WO2008121063, WO2008121064, EP-1992620,EP-1992621, EP1992624, EP-1992625, WO2008130312, WO2009007029,EP2020232, WO2009017452, WO2009035634, WO2009035684, WO2009038385,WO2009095787, WO2009095788, WO2009095789, WO2009095792, WO2009145814,US2009291982, WO2009154697, WO2009156857, WO2009156859, WO2009156860,WO2009156861, WO2009156863, WO2009156864, WO2009156865, WO2010013168,WO2010014794.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), for example those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoinositide kinase-3 (PI3K), forexample those as described in WO2008027584, WO2008070150, WO2008125833,WO2008125835, WO2008125839, WO2009010530, WO2009026345, WO2009071888,WO2009071890, WO2009071895.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of serum/glucocorticoid-regulated kinase(SGK), as described, for example, in WO2006072354, WO2007093264,WO2008009335, WO2008086854, WO2008138448.

In one embodiment, the compound of the formula I is administered incombination with a modulator of the glucocorticoid receptor, asdescribed, for example, in WO2008057855, WO2008057856, WO2008057857,WO2008057859, WO2008057862, WO2008059867, WO2008059866, WO2008059865,WO2008070507, WO2008124665, WO2008124745, WO2008146871, WO2009015067,WO2009040288, WO2009069736, WO2009149139.

In one embodiment, the compound of the formula I is administered incombination with a modulator of the mineralocorticoid receptor (MR), forexample drospirenone, or those as described in WO2008104306,WO2008119918.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta), forexample ruboxistaurin, or those as described in WO2008096260,WO2008125945.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase D, for example doxazosin(WO2008088006).

In a further embodiment, the compound of the formula I is administeredin combination with an activator/modulator of the AMP-activated proteinkinase (AMPK), as described, for example, in WO2007062568, WO2008006432,WO2008016278, WO2008016730, WO2008020607, WO2008083124, WO2008136642,WO2009019445, WO2009019446, WO2009019600, WO2009028891, WO2009065131,WO2009076631, WO2009079921, WO2009100130, WO2009124636, WO2009135580,WO2009152909.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of ceramide kinase, as described, forexample, in WO2007112914, WO2007149865.

In a further embodiment, the compound of the formula I is administeredin combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1or 2), as described, for example, in WO2007104053, WO2007115822,WO2008008547, WO2008075741.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “I-kappaB kinase” (IKK inhibitors), asdescribed, for example, in WO2001000610, WO2001030774, WO2004022057,WO2004022553, WO2005097129, WO2005113544, US2007244140, WO2008099072,WO2008099073, WO2008099073, WO2008099074, WO2008099075, WO2009056693,WO2009075277, WO2009089042, WO2009120801.

In another embodiment, the compound of the formula I is administered incombination with inhibitors of NF-kappaB (NFKB) activation, for examplesalsalate.

In a further embodiment, the compound of the formula I is administeredin combination with inhibitors of ASK-1 (apoptosis signal-regulatingkinase 1), as described, for example, in WO2008016131, WO2009123986.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950,NCX-6560, or those as described in US2007249583, WO2008083551,WO2009054682.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a farnesoid X receptor (FXR)modulator, for example WAY-362450 or those as described in WO2003099821,WO2005056554, WO2007052843, WO2007070796, WO2007092751, JP2007230909,WO2007095174, WO2007140174, WO2007140183, WO2008000643, WO2008002573,WO2008025539, WO2008025540, JP2008214222, JP2008273847, WO2008157270,US2008299118, US2008300235, WO2009005998, WO2009012125, WO2009027264,WO2009062874, US2009131409, US2009137554, US2009163552, WO2009127321,EP2128158.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a ligand of the liver X receptor (LXR),as described, for example, in WO2007092965, WO2008041003, WO2008049047,WO2008065754, WO2008073825, US2008242677, WO2009020683, US2009030082,WO2009021868, US2009069373, WO2009024550, WO2009040289, WO2009086123,WO2009086129, WO2009086130, WO2009086138, WO2009107387, US2009247587,WO2009133692, WO2008138438, WO2009144961, WO2009150109.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate, for example fenofibrate,clofibrate, bezafibrate, or those as described in WO2008093655.

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate (SLV-348; Trilipix™).

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate (Trilipix™) and an HMG-CoA reductase inhibitor, forexample rosuvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with bezafibrate and diflunisal.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of fenofibrateor a salt thereof with simvastatin, rosuvastatin, fluvastatin,lovastatin, cerivastatin, pravastatin, pitavastatin or atorvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with Synordia®, a solid combination offenofibrate with metformin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of metformin withan MTP inhibitor, as described in WO2009090210.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol reabsorption inhibitor,for example ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464,WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 orWO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon BiotechnologyAG), or as described in WO2002050060, WO2002050068, WO2004000803,WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248,WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186,WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782,WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163,WO2007059871, US2007232688, WO2007126358, WO2008033431, WO2008033465,WO2008052658, WO2008057336, WO2008085300, WO2008104875, US2008280836,WO2008108486.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an NPC1L1 antagonist, for example thoseas described in WO2008033464, WO2008033465.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a solid combination ofezetimibe with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withatorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withfenofibrate.

In one embodiment of the invention, the further active ingredient is adiphenylazetidinone derivative, as described, for example, in U.S. Pat.No. 6,992,067 or U.S. Pat. No. 7,205,290.

In a further embodiment of the invention, the further active ingredientis a diphenylazetidinone derivative, as described, for example, in U.S.Pat. No. 6,992,067 or U.S. Pat. No. 7,205,290, combined with a statin,for example simvastatin, fluvastatin, pravastatin, lovastatin,cerivastatin, atorvastatin, pitavastatin or rosuvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of lapaquistat, asqualene synthase inhibitor, with atorvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a conjugate consisting of theHMG-CoA reductase inhibitor atorvastatin with the renin inhibitoraliskiren (WO2009090158).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor, for exampletorcetrapib, anacetrapib or JTT-705 (dalcetrapib), or those as describedin WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362,WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154,US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243,WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906,WO2008006257, WO2008009435, WO2008018529, WO2008058961, WO2008058967,WO2008059513, WO2008070496, WO2008115442, WO2008111604, WO2008129951,WO2008141077, US2009118287, WO2009062371, WO2009071509.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bile acid reabsorption inhibitors(inhibitors of the intestinal bile acid transporter (IBAT)) (see, forexample, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), for example HMR 1741, or those as described in DE 10 2005033099.1 and DE 10 2005 033100.9, DE 10 2006 053635, DE 10 2006 053637,WO2007009655-56, WO2008058628, WO2008058629, WO2008058630, WO2008058631.

In one embodiment, the compound of the formula I is administered incombination with agonists of GPBAR1 (G-protein-coupled bile acidreceptor 1; TGR5), for example INT-777 or those as described, forexample, in US20060199795, WO2007110237, WO2007127505, WO2008009407,WO2008067219, WO2008067222, FR2908310, WO2008091540, WO2008097976,US2009054304, WO2009026241, WO2009146772, WO2010014739, WO2010014836.

In one embodiment, the compound of the formula I is administered incombination with modulators of histone deacetylase, for exampleursodeoxycholic acid, as described in WO2009011420.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPM5 channel (TRP cationchannel M5), as described, for example, in WO2008097504, WO2009038722.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPA1 channel (TRP cationchannel A1), as described, for example, in US2009176883, WO2009089083,WO2009144548.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPV3 channel (TRP cationchannel V3), as described, for example, in WO2009084034, WO2009130560.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber, forexample cholestyramine, colesevelam hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with colesevelam hydrochloride and metforminor a sulfonylurea or insulin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with tocotrienol and insulin or an insulinderivative.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a chewing gum comprising phytosterols(Reductol™).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of the microsomaltriglyceride transfer protein (MTP inhibitor), for example implitapide,BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, JTT-130, or thoseas described in WO2005085226, WO2005121091, WO2006010423, WO2006113910,WO2007143164, WO2008049806, WO2008049808, WO2008090198, WO2008100423,WO2009014674.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a combination of a cholesterolabsorption inhibitor, for example ezetimibe, and an inhibitor of thetriglyceride transfer protein (MTP inhibitor), for example implitapide,as described in WO2008030382 or in WO2008079398.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an active antihypertriglyceridemicingredient, for example those as described in WO2008032980.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an antagonist of the somatostatin 5receptor (SSTS receptor), for example those as described inWO2006094682.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor, for exampleavasimibe, SMP-797 or KY-382, or those as described in WO2008087029,WO2008087030, WO2008095189, WO2009030746, WO2009030747, WO2009030750,WO2009030752, WO2009070130, WO2009081957, WO2009081957.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an inhibitor of liver carnitinepalmitoyltransferase-1 (L-CPT1), as described, for example, inWO2007063012, WO2007096251 (ST-3473), WO2008015081, US2008103182,WO2008074692, WO2008145596, WO2009019199, WO2009156479, WO2010008473.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of carnitinO-palmitoyltransferase II (CPT2), as described, for example, inUS2009270500, US2009270505, WO2009132978, WO2009132979.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a modulator of serinepalmitoyltransferase (SPT), as described, for example, in WO2008031032,WO2008046071, WO2008083280, WO2008084300.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor, forexample BMS-188494, TAK-475 (lapaquistat acetate), or as described inWO2005077907, JP2007022943, WO2008003424, WO2008132846, WO2008133288,WO2009136396.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012 (mipomersen), an antisenseoligonucleotide which is capable of regulating the apolipoprotein Bgene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with apolipoprotein (ApoB) SNALP, atherapeutic product which comprises an siRNA (directed against the ApoBgene).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a stimulator of the ApoA-1 gene, asdescribed, for example, in WO2008092231.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a modulator of the synthesis ofapolipoprotein C-III, for example ISIS-APOCIIIRx.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), for example HMR1171, HMR1586, or those as described inWO2005097738, WO2008020607.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an HDL cholesterol-elevating agent, forexample those as described in WO2008040651, WO2008099278, WO2009071099,WO2009086096, US2009247550.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ABCA1 expression enhancer, asdescribed, for example, in WO2006072393, WO2008062830, WO2009100326.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator, forexample ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist, forexample gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor, for exampleorlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A1 receptor agonist(adenosine A1 R), for example CVT-3619 or those as described, forexample, in EP1258247, EP1375508, WO2008028590, WO2008077050,WO2009050199, WO2009080197, WO2009100827, WO2009112155.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor agonist(adenosine A2B R), for example ATL-801.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a modulator of adenosine A2A and/oradenosine A3 receptors, as described, for example, in WO2007111954,WO2007121918, WO2007121921, WO2007121923, WO2008070661, WO2009010871.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a ligand of the adenosine A1/A2Breceptors, as described, for example, in WO2008064788, WO2008064789,WO2009080198, WO2009100827, WO2009143992.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor antagonist(adenosine A2B R), as described in US2007270433, WO2008027585,WO2008080461, WO2009037463, WO2009037467, WO2009037468, WO2009118759.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC1 and/orACC2), for example those as described in WO199946262, WO200372197,WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809,WO2007011811, WO2007013691, WO2007095601-603, WO2007119833,WO2008065508, WO2008069500, WO2008070609, WO2008072850, WO2008079610,WO2008088688, WO2008088689, WO2008088692, US2008171761, WO2008090944,JP2008179621, US2008200461, WO2008102749, WO2008103382, WO2008121592,WO2009082346, US2009253725, JP2009196966, WO2009144554, WO2009144555,WO2010003624, WO2010002010.

In another embodiment, the compound of the formula I is administered incombination with modulators of microsomal acyl-CoA:glycerol-3-phosphateacyltransferase 3 (GPAT3, described in WO2007100789) or with modulatorsof microsomal acyl-CoA:glycerol-3-phosphate acyltransferase 4 (GPAT4,described in WO2007100833) or with modulators of mitochondrialglycerol-3-phosphate O-acyltransferase, described in WO2010005922.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of xanthine oxidoreductase (XOR).

In another embodiment, the compound of the formula I is administered incombination with inhibitors of soluble epoxide hydrolase (sEH), asdescribed, for example, in WO2008051873, WO2008051875, WO2008073623,WO2008094869, WO2008112022, WO2009011872, WO2009049154, WO2009049157,WO2009049165, WO2009073772, WO2009097476, WO2009111207, WO2009129508,WO2009151800.

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

NPY antagonists, for example4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethylnaphthalene-1-sulfonamidehydrochloride (CGP 71683A) or velneperit or those as described inWO2009110510;

NPY-5 receptor antagonists/receptor modulators, such as L-152804 or thecompound “NPY-5-BY” from Banyu, or as described, for example, inWO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026564,WO2008052769, WO2008092887, WO2008092888, WO2008092891, WO2008129007,WO2008134228, WO2009054434, WO2009095377, WO2009131096;NPY-4 receptor antagonists, as described, for example, in WO2007038942;NPY-2 receptor antagonists/modulators, as described, for example, inWO2007038943, WO2009006185, US2009099199, US2009099243, US2009099244,WO2009079593, WO2009079597;peptide YY 3-36 (PYY3-36) or analogous compounds, for example CJC-1682(PYY3-36 conjugated with human serum albumin via Cys34) or CJC-1643(derivative of PYY3-36, which is conjugated in vivo to serum albumin),or those as described in WO2005080424, WO2006095166, WO2008003947,WO2009080608;NPY-2 receptor agonists, as described, for example, in WO2009080608;derivatives of the peptide obestatin, as described by WO2006096847;CB1R (cannabinoid receptor 1) antagonists/inverse agonists, for examplerimonabant, surinabant (SR147778), SLV-319 (ibipinabant), AVE-1625,taranabant (MK-0364) or salts thereof, otenabant (CP-945,598),rosonabant, V-24343 or those compounds as described in, for example, EP0656354, WO 00/15609, WO2001/64632-64634, WO 02/076949, WO2005080345,WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700,WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069,U.S. Pat. No. 6,509,367, WO200132663, WO2003086288, WO2003087037,WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744,WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255,WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856,WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157,US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820,US20050009870, WO200500974, WO2004111033-34, WO200411038-39,WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837,WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006018662,WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480,WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704,WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007018460,WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720,WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810,WO2007046548, WO2007047737, WO2007057687, WO2007062193, WO2007064272,WO2007079681, WO2007084319, WO2007084450, WO2007086080, EP1816125,US2007213302, WO2007095513, WO2007096764, US2007254863, WO2007119001,WO2007120454, WO2007121687, WO2007123949, US2007259934, WO2007131219,WO2007133820, WO2007136571, WO2007136607, WO2007136571, U.S. Pat. No.7,297,710, WO2007138050, WO2007139464, WO2007140385, WO2007140439,WO2007146761, WO2007148061, WO2007148062, US2007293509, WO2008004698,WO2008017381, US2008021031, WO2008024284, WO2008031734, WO2008032164,WO2008034032, WO2008035356, WO2008036021, WO2008036022, WO2008039023,WO2998043544, WO2008044111, WO2008048648, EP1921072-A1, WO2008053341,WO2008056377, WO2008059207, WO2008059335, WO2008062424, WO2008068423,WO2008068424, WO2008070305, WO2008070306, WO2008074816, WO2008074982,WO2008075012, WO2008075013, WO2008075019, WO2008075118, WO2008076754,WO2008081009, WO2008084057, EP1944295, US2008090809, US2008090810,WO2008092816, WO2008094473, WO2008094476, WO2008099076, WO2008099139,WO2008101995, US2008207704, WO2008107179, WO2008109027, WO2008112674,WO2008115705, WO2008118414, WO2008119999, WO200812000, WO2008121257,WO2008127585, WO2008129157, WO2008130616, WO2008134300, US2008262066,US2008287505, WO2009005645, WO2009005646, WO2009005671, WO2009023292,WO2009023653, WO2009024819, WO2009033125, EP2042175,WO2009053548-WO2009053553, WO2009054923, WO2009054929, WO2009059264,WO2009073138, WO2009074782, WO2009075691, WO2009078498, WO2009087285,WO2009074782, WO2009097590, WO2009097995, WO2009097996, WO2009097998,WO2009097999, WO2009098000, WO2009106708, US2009239909, WO2009118473,US2009264436, US2009264476, WO2009130234, WO2009131814, WO2009131815,US2009286758, WO2009141532, WO2009141533, WO2009153569, WO2010003760,WO2010012437, WO2010019762;cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) modulatingcompounds, for example delta-9-tetrahydrocannabivarin, or those asdescribed, for example, in WO2007001939, WO2007044215, WO2007047737,WO2007095513, WO2007096764, WO2007112399, WO2007112402, WO2008122618,WO2009007697, WO2009012227, WO2009087564, WO2009093018, WO2009095752,WO2009120660, WO2010012964;cannabinoid receptor 2 (CB2) modulating compounds, for example those asdescribed, for example, in WO2008063625, WO2008157500, WO2009004171,WO2009032754, WO2009055357, WO2009061652, WO2009063495, WO2009067613WO2009114566;modulators of FAAH (fatty acid amide hydrolase), as described, forexample, in WO2007140005, WO2008019357, WO2008021625, WO2008023720,WO2008030532, WO2008129129, WO2008145839, WO2008145843, WO2008147553,WO2008153752, WO2009011904, WO2009048101, WO2009084970, WO2009105220,WO2009109504, WO2009109743, WO2009117444, WO2009127944, WO2009138416,WO2009151991, WO2009152025, WO2009154785, WO2010005572, WO2010017079;inhibitors of fatty acid synthase (FAS), as described, for example, inWO2008057585, WO2008059214, WO2008075064, WO2008075070, WO2008075077,WO2009079860;inhibitors of LCE (long chain fatty acid elongase)/long chain fatty acidCoA ligase, as described, for example, in WO2008120653, WO2009038021,WO2009044788, WO2009081789, WO2009099086;vanilloid-1 receptor modulators (modulators of TRPV1), as described, forexample, in WO2007091948, WO2007129188, WO2007133637, WO2008007780,WO2008010061, WO2008007211, WO2008010061, WO2008015335, WO2008018827,WO2008024433, WO2008024438, WO2008032204, WO2008050199, WO2008059339,WO2008059370, WO2008066664, WO2008075150, WO2008090382, WO2008090434,WO2008093024, WO2008107543, WO2008107544, WO2008110863, WO2008125295,WO2008125296, WO2008125337, WO2008125342, WO2008132600, WO2008133973,WO2009010529, WO2009010824, WO2009016241, WO2009023539, WO2009038812,WO2009050348, WO2009055629, WO2009055749, WO2009064449, WO2009081222,WO2009089057, WO2009109710, WO2009112677, WO2009112678, WO2009112679,WO2009121036, WO2009124551, WO2009136625, WO2010002209;modulators, ligands, antagonists or inverse agonists of the opioidreceptors, for example GSK-982 or those as described, for example, inWO2007047397, WO2008021849, WO2008021851, WO2008032156, WO2008059335,WO2008125348, WO2008125349, WO2008142454, WO2009030962, WO2009103552,WO2009115257;modulators of the “orphan opioid (ORL-1) receptor”, as described, forexample, in US2008249122, WO2008089201;agonists of the prostaglandin receptor, for example bimatoprost or thosecompounds as described in WO2007111806;MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists,for exampleN-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141, MK-0493, or those as described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2004089307, WO2005042516,WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184,WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573,EP1538159, WO2004072076, WO2004072077, WO2006021655-57, WO2007009894,WO2007015162, WO2007041061, WO2007041052, JP2007131570, EP-1842846,WO2007096186, WO2007096763, WO2007141343, WO2008007930, WO2008017852,WO2008039418, WO2008087186, WO2008087187, WO2008087189,WO2008087186-WO2008087190, WO2008090357, WO2008142319, WO2009015867,WO2009061411, US2009076029, US2009131465, WO2009071101, US2009305960,WO2009144432, WO2009151383, WO2010015972;MC4 receptor modulators (melanocortin-4 receptor modulators), asdescribed, for example, in WO2009010299, WO2009074157;orexin receptor 1 antagonists (OX1R antagonists), orexin receptor 2antagonists (OX2R antagonists) or mixed OX1R/OX2R antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A), or those as described, for example, in WO200196302,WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718,WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935,WO2008008517, WO2008008518, WO2008008551, WO2008020405, WO2008026149,WO2008038251, US2008132490, WO2008065626, WO2008078291, WO2008087611,WO2008081399, WO2008108991, WO2008107335, US2008249125, WO2008147518,WO2008150364, WO2009003993, WO2009003997, WO2009011775, WO2009016087,WO2009020642, WO2009058238, US2009186920, US2009203736, WO2009092642,WO2009100994, WO2009104155, WO2009124956, WO2009133522, WO2009156951,WO2010017260);histamine H3 receptor antagonists/inverse agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208), or those as described in WO200064884,WO2005082893, WO2005123716, US2005171181 (e.g. PF-00389027),WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798,WO2007055418, WO2007057329, WO2007062999, WO2007065820, WO2007068620,WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450,WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053,WO2007106349, WO2007110364, WO2007115938, WO2007131907, WO2007133561,US2007270440, WO2007135111, WO2007137955, US2007281923, WO2007137968,WO2007138431, WO2007146122, WO2008005338, WO2008012010, WO2008015125,WO2008045371, EP1757594, WO2008068173, WO2008068174, US20080171753,WO2008072703, WO2008072724, US2008188484, US2008188486, US2008188487,WO2008109333, WO2008109336, WO2008126886, WO2008154126, WO2008151957,US2008318952, WO2009003003, WO2009013195, WO2009036132, WO2009039431,WO2009045313, WO2009058300, WO2009063953, WO2009067401, WO2009067405,WO2009067406, US2009163464, WO2009100120, WO2009105206, WO2009121812,WO2009126782, WO2010011653, WO2010011657);histamine H1/histamine H3 modulators, for example betahistine or itsdihydrochloride;modulators of the histamine H3 transporter or of the histamineH3/serotonin transporter, as described, for example, in WO2008002816,WO2008002817, WO2008002818, WO2008002820;modulators of vesicular monoamine transporter 2 (VMAT2), as described,for example, in WO2009126305;histamine H4 modulators, as described, for example, in WO2007117399,US2009156613;CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585) or those CRF1 antagonists as described in WO2007105113,WO2007133756, WO2008036541, WO2008036579, WO2008083070, WO2010015628,WO2010015655);CRF BP antagonists (e.g. urocortin);urocortin agonists;modulators of the beta-3 adrenoceptor, for example1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451) or solabegron (GW-427353) or N-5984(KRP-204), or those as described in JP2006111553, WO2002038543,WO2002038544, WO2007048840-843, WO2008015558, EP1947103, WO2008132162;MSH (melanocyte-stimulating hormone) agonists;MCH (melanine-concentrating hormone) receptor antagonists (for exampleNBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71 (AMG-071,AMG-076), GW-856464, NGD-4715, ATC-0453, ATC-0759, GW-803430, or thosecompounds as described in WO2005085200, WO2005019240, WO2004011438,WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925,WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729,WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680,WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279,WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847,WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669,US2007093508, US2007093509, WO2007048802, JP2007091649, WO2007092416;WO2007093363-366, WO2007114902, WO2007114916, WO2007141200,WO2007142217, US2007299062, WO2007146758, WO2007146759, WO2008001160,WO2008016811, WO2008020799, WO2008022979, WO2008038692, WO2008041090,WO2008044632, WO2008047544, WO2008061109, WO2008065021, WO2008068265,WO2008071646, WO2008076562, JP2008088120, WO2008086404, WO2008086409,US2008269110, WO2008140239, WO2009021740, US2009011994, US2009082359,WO2009041567, WO2009076387, WO2009089482, WO2009103478, WO2009119726,WO2009120655, WO2009123194, WO2009137270, WO2009146365, WO2009154132);CCK-A (CCK-1) modulators (for example{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150)or SSR-125180) or those as described in WO2005116034, WO2007120655,WO2007120688, WO2007120718, WO2008091631;serotonin reuptake inhibitors (e.g. dexfenfluramine), or those asdescribed in WO2007148341, WO2008034142, WO2008081477, WO2008120761,WO2008141081, WO2008141082, WO2008145135, WO2008150848, WO2009043834,WO2009077858;mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion), or thoseas described in WO2008063673, or solid combinations of bupropion withnaltrexone or bupropion with zonisamide;mixed reuptake inhibitors, for example DOV-21947 or those as describedin WO2009016214, WO2009016215, WO2009077584, WO2009098208, WO2009098209,WO2009106769, WO2009109517, WO2009109518, WO2009109519, WO2009109608,WO2009145357, WO2009149258;mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid salt (WO 01/09111);mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g.tesofensine), or those as described, for example, in WO2006085118,WO2008150480;dopamine antagonists, as described, for example, in WO2008079838,WO2008079839, WO2008079847, WO2008079848;norepinephrine reuptake inhibitors, as described, for example, inUS2008076724, WO2009062318;5-HT1A receptor modulators, as described, for example, in WO2009006227,WO2009137679, WO2009137732;5-HT2A receptor antagonists, as described, for example, in WO2007138343;5-HT2C receptor agonists (for example lorcaserine hydrochloride(APD-356) or BVT-933, or those as described in WO200077010,WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533,WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025,WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007132841,WO2007140213, WO2008007661, WO2008007664, WO2008009125, WO2008010073,WO2008108445, WO2009063991, WO2009063992, WO2009063993, WO2009079765);5-HT6 receptor modulators, for example E-6837, BVT-74316, PF-3246799 orPRX-07034, or those as described, for example, in WO2005058858,WO2007054257, WO2007107373, WO2007108569, WO2007108742-744,WO2008003703, WO2008027073, WO2008034815, WO2008054288, EP1947085,WO2008084491, WO2008084492, WO2008092665, WO2008092666, WO2008101247,WO2008110598, WO2008116831, WO2008116833, WO2008117169, WO2008136017,WO2008147812, EP2036888, WO2009013010, WO2009034581, WO2009053997,WO2009056632, WO2009073118, WO2009115515, WO2009135925, WO2009135927,WO2010000456, WO2010012806, EP2145887;agonists of estrogen receptor gamma (ERRγ agonists), as described, forexample, in WO2007131005, WO2008052709;agonists of estrogen receptor alpha (ERRα/ERR1 agonists), as described,for example, in WO2008109727;agonists of estrogen receptor beta (ERRβ agonists), as described, forexample, in WO2009055734, WO2009100335, WO2009127686;sigma-1 receptor antagonists, as described, for example, inWO2007098953, WO2007098961, WO2008015266, WO2008055932, WO2008055933,WO2009071657;muscarin 3 receptor (M3R) antagonists, as described, for example, inWO2007110782, WO2008041184;bombesin receptor agonists (BRS-3 agonists), as described, for example,in WO2008051404, WO2008051405, WO2008051406, WO2008073311;galanin receptor antagonists;growth hormone (e.g. human growth hormone or AOD-9604);growth hormone releasing compounds (tert-butyl6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));growth hormone secretagogue receptor antagonists (ghrelin antagonists),for example A-778193, or those as described in WO2005030734,WO2007127457, WO2008008286, WO2009056707;growth hormone secretagogue receptor modulators (ghrelin modulators),for example JMV-2959, JMV-3002, JMV-2810, JMV-2951, or those asdescribed in WO2006012577 (e.g. YIL-781 or YIL-870), WO2007079239,WO2008092681, WO2008145749, WO2008148853, WO2008148854, WO2008148856,WO2009047558, WO2009071283, WO2009115503;TRH agonists (see, for example, EP 0 462 884);decoupling protein 2 or 3 modulators (as described, for example, inWO2009128583);chemical decouplers (e.g. WO2008059023, WO2008059024, WO2008059025,WO2008059026);leptin receptor agonists (see, for example, Lee, Daniel W.; Leinung,Matthew C.; Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonistsas a potential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);leptin receptor modulators, as described, for example, in WO2009019427,WO2009071658, WO2009071668, WO2009071677, WO2009071678, WO2009147211,WO2009147216, WO2009147219, WO2009147221;DA agonists (bromocriptin, bromocriptin mesylate, doprexin) or those asdescribed in US2009143390;lipase/amylase inhibitors (e.g. WO 00/40569, WO2008107184, WO2009049428,WO2009125819);inhibitors of diacylglycerol O-acyltransferases (DGATs), for exampleBAY-74-4113, or as described, for example, in US2004/0224997,WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952,WO2006120125, WO2006113919, WO2006134317, WO2007016538, WO2007060140,JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107,WO2007138304, WO2007138311, WO2007141502, WO2007141517, WO2007141538,WO2007141545, WO2007144571, WO2008011130, WO2008011131, WO2008039007,WO2008048991, WO2008067257, WO2008099221, WO2008129319, WO2008141976,WO2008148840, WO2008148849, WO2008148851, WO2008148868, WO2009011285,WO2009016462, WO2009024821, US2009076275, WO2009040410, WO2009071483,WO2009081195, WO2009119534, WO2009126624, WO2009126861, WO2010007046,WO2010017040;inhibitors of monoacylglycerol acyltransferase (2-acylglycerolO-acyltransferase; MGAT), as described, for example, in WO2008038768;inhibitors of fatty acid synthase (FAS), for example C75, or those asdescribed in WO2004005277, WO2008006113;inhibitors of stearoyl-CoA delta9 desaturase (SCD1), as described, forexample, in WO2007009236, WO2007044085, WO2007046867, WO2007046868,WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457,WO2007136746, WO2007143597, WO2007143823, WO2007143824, WO2008003753,WO2008017161, WO2008024390, WO2008029266, WO2008036715, WO2008043087,WO2008044767, WO2008046226, WO2008056687, WO2008062276, WO2008064474,WO2008074824, WO2008074832, WO2008074833, WO2008074834, WO2008074835,WO2008089580, WO2008096746, WO2008104524, WO2008116898, US2008249100,WO2008120744, WO2008120759, WO2008123469, WO2008127349, WO2008128335,WO2008135141, WO2008139845, WO2008141455, US20080255130, US2008255161,WO2008141455, WO2009010560, WO2009016216, WO2009012573, WO2009024287,JP2009019013, WO2009037542, WO2009056556, WO2009060053, WO2009060054,WO2009070533, WO2009073973, WO2009103739, WO2009117659, WO2009117676,US2009253693, US2009253738, WO2009124259, WO2009126123, WO2009126527,WO2009129625, WO2009137201, WO2009150196, WO2009156484, WO2010006962,WO2010007482;inhibitors of fatty acid desaturase 1 (deltas desaturase), as described,for example, in WO2008089310;inhibitors of monoglyceride lipase (MGL), as described in WO2008145842;hypoglycemic/hypertriglyceridemic indoline compounds, as described inWO2008039087, WO2009051119;inhibitors of “adipocyte fatty acid-binding protein aP2”, for exampleBMS-309403 or those as described in WO2009028248;activators of adiponectin secretion, as described, for example, inWO2006082978, WO2008105533, WO2008136173;promoters of adiponectin production, as described, for example, inWO2007125946, WO2008038712;modified adiponectins, as described, for example, in WO2008121009;oxyntomodulin or analogs thereof (for example, TKS-1225);oleoyl-estroneor agonists or partial agonists of the thyroid hormone receptor (thyroidhormone receptor agonists), for example: KB-2115 (eprotirome), QRX-431(sobetirome) or DITPA, or those as described in WO20058279, WO200172692,WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419,WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492,WO2007132475, WO2007134864, WO2008001959, WO2008106213, JP2009155261;or agonists of the thyroid hormone receptor beta (TR-beta), for exampleMB-07811 or MB-07344, or those as described in WO2008062469.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a combination of eprotirome withezetimibe.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of site-1 protease (SIP),for example PF-429242.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a modulator of the “trace amineassociated receptor 1” (TAAR1), as described, for example, inUS2008146523, WO2008092785.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of growth factor receptorbound protein 2 (GRB2), as described, for example, in WO2008067270.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an RNAi (siRNA) therapeutic agentdirected against PCSK9 (proprotein convertase subtilisin/kexin type 9).

In one embodiment, the compound of the formula I is administered incombination with Omacor® or Lovaza™ (omega-3 fatty acid ester; highlyconcentrated ethyl ester of eicosapentaenoic acid and of docosahexaenoicacid).

In one embodiment, the compound of the formula I is administered incombination with lycopene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant, for example OPC-14117,AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, β-caroteneor selenium, or those as described in WO2009135918.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin, for example vitamin B6 orvitamin B12.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, forexample in combination with a sulfonylurea and metformin, a sulfonylureaand acarbose, repaglinide and metformin (PrandiMet™), insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

In a further embodiment, the compound of the formula I is administeredin combination with an activator of soluble guanylate cyclase (sGC), asdescribed, for example, in WO2009032249.

In another embodiment, the compound of the formula I is administered incombination with an inhibitor of carboanhydrase type 2 (carbonicanhydrase type 2), for example those as described in WO2007065948,WO2009050252.

In another embodiment, the compound of the formula I is administered incombination with topiramat or a derivative thereof, as described inWO2008027557, US2009304789.

In a further embodiment, the compound of the formula I is administeredin combination with a solid combination of topiramat with phentermin(Qnexa™).

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-377131, whichinhibits the production of the glucocorticoid receptor.

In another embodiment, the compound of the formula I is administered incombination with an aldosterone synthase inhibitor and an antagonist ofthe glucocorticoid receptor, a cortisol synthesis inhibitor and/or anantagonist of the corticotropin releasing factor, as described, forexample, in EP1886695, WO2008119744.

In one embodiment, the compound of the formula I is administered incombination with an agonist of the RUP3 receptor, as described, forexample, in WO2007035355, WO2008005576.

In another embodiment, the compound of the formula I is administered incombination with an activator of the gene which codes for ataxiatelangiectasia mutated (ATM) protein kinase, for example chloroquine.

In one embodiment, the compound of the formula I is administered incombination with a tau protein kinase 1 inhibitor (TPK1 inhibitor), asdescribed, for example, in WO2007119463, WO2009035159, WO2009035162.

In one embodiment, the compound of the formula I is administered incombination with a “c-Jun N-terminal kinase” inhibitor (JNK inhibitor),for example B1-78D3 or those as described, for example, in WO2007125405,WO2008028860, WO2008118626.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist, for exampleavosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of neutral endopeptidase (NEP inhibitors),as described, for example, in WO2009138122, WO2009135526.

In one embodiment, the compound of the formula I is administered incombination with modulators of the glucocorticoid receptor (GR), forexample KB-3305 or those compounds as described, for example, inWO2005090336, WO2006071609, WO2006135826, WO2007105766, WO2008120661,WO2009040288, WO2009058944, WO2009108525, WO2009111214.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is an agonist of thealpha 7-nicotinic acetylcholine receptor, as described, for example, inWO2009018551, WO2009071519, WO2009071576, WO2009071577.

In one embodiment, the further active ingredient is trodusquemine.

In one embodiment, the further active ingredient is a modulator of theenzyme SIRT1 and/or SIRT3 (an NAD⁺-dependent protein deacetylase); thisactive ingredient may, for example, be resveratrol in suitableformulations, or those compounds as specified in WO2007019416 (e.g.SRT-1720), WO2008073451, WO2008156866, WO2008156869, WO2009026701,WO2009049018, WO2009058348, WO2009061453, WO2009134973, WO2009146358,WO2010003048.

In one embodiment of the invention, the further active ingredient isDM-71 (N-acetyl-L-cysteine with bethanechol).

In one embodiment, the compound of the formula I is administered incombination with antihypercholesterolemic compounds, as described, forexample, in WO2004000803, WO2006000804, WO2004000805, WO2004087655,WO2005113496, WO2007059871, WO2007107587, WO2007111994, WO2008052658,WO2008106600, WO2008113796, US2008280836, WO2009113952, US2009312302

In a further embodiment, the compound of the formula I is administeredin combination with inhibitors of SREBP (sterol regulatoryelement-binding protein), for example fatostatin, or those as described,for example, in WO2008097835.

In another embodiment, the compound of the formula I is administered incombination with a cyclic peptide agonist of the VPAC2 receptor, asdescribed, for example, in WO2007101146, WO2007133828.

In a further embodiment, the compound of the formula I is administeredin combination with an agonist of the endothelin receptor, as described,for example, in WO2007112069.

In a further embodiment, the compound of the formula I is administeredin combination with AKP-020 (bis(ethylmaltolato)oxovanadium(IV)).

In another embodiment, the compound of the formula I is administered incombination with tissue-selective androgen receptor modulators (SARM),as described, for example, in WO2007099200, WO2007137874.

In a further embodiment, the compound of the formula I is administeredin combination with an AGE (advanced glycation endproduct) inhibitor, asdescribed, for example, in JP2008024673.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In another embodiment of the invention, the further active ingredient ismetreleptin (recombinant methionyl-leptin) combined with pramlintide.

In a further embodiment of the invention, the further active ingredientis the tetrapeptide ISF-402.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine orthose derivatives as described in WO2008034142.

In one embodiment, the further active ingredient is mazindol orphentermin.

In a further embodiment, the further active ingredient is geniposidicacid (WO2007100104) or derivatives thereof (JP2008106008).

In another embodiment, the further active ingredient is a neuropeptideFF2 agonist, as described, for example, in WO2009038012.

In one embodiment, the further active ingredient is a nasal calciumchannel blocker, for example diltiazem, or those as described in U.S.Pat. No. 7,138,107.

In one embodiment, the further active ingredient is an inhibitor ofsodium-calcium ion exchange, for example those as described inWO2008028958, WO2008085711.

In a further embodiment, the further active ingredient is a blocker ofcalcium channels, for example of CaV3.2 or CaV2.2, as described inWO2008033431, WO2008033447, WO2008033356, WO2008033460, WO2008033464,WO2008033465, WO2008033468, WO2008073461.

In one embodiment, the further active ingredient is a modulator of acalcium channel, for example those as described in WO2008073934,WO2008073936, WO2009107660.

In one embodiment, the further active ingredient is an inhibitor of thecalcium metabolism, for example those as described in US2009124680.

In one embodiment, the further active ingredient is a blocker of the“T-type calcium channel”, as described, for example, in WO2008033431,WO2008110008, US2008280900, WO2008141446, US2009270338, WO2009146540,US2009325979, WO2009146539.

In one embodiment, the further active ingredient is an inhibitor of KCNQpotassium channel 2 or 3, for example those as described inUS2008027049, US2008027090.

In one embodiment, the further active ingredient is a modulator of KCNNpotassium channel 1, 2 or 3 (modulators of the SK1, SK2 and/or SK3channel), for example those as described in US2009036475.

In one embodiment, the further active ingredient is an inhibitor of thepotassium Kv1.3 ion channel, for example those as described inWO2008040057, WO2008040058, WO2008046065, WO2009043117.

In one embodiment, the further active ingredient is a potassium channelmodulator, for example those as described in WO2008135447, WO2008135448,WO2008135591, WO2009099820.

In a further embodiment, the further active ingredient is ahyperpolarization-activated cyclic nucleotide-gated (HCN)potassium-sodium channel inhibitor, for example those as described inUS2009069296.

In another embodiment, the further active ingredient is an inhibitor ofthe sodium-potassium-2 chloride (NKCCl) cotransporter, for example thoseas described in WO2009130735.

In another embodiment, the further active ingredient is a voltage-gatedsodium channel inhibitor, for example those as described inWO2009049180, WO2009049181.

In another embodiment, the further active ingredient is a modulator ofthe MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-1)), forexample those as described in WO2008014360, WO2008014381.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 3 (SSTR3), for example those as described inWO2009011836.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 5 (SSTR5), for example those as described inWO2008019967, US2008064697, US2008249101, WO2008000692, US2008293756,WO2008148710.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 2 (SSTR2), for example those as described inWO2008051272.

In one embodiment, the further active ingredient is a compound which iscapable of reducing the amount of retinol-binding protein 4 (RBP4), forexample those as described in WO2009051244, WO2009145286.

In one embodiment, the further active ingredient is anerythropoietin-mimetic peptide which acts as an erythropoietin (EPO)receptor agonist. Such molecules are described, for example, inWO2008042800.

In a further embodiment, the further active ingredient is an anorectic/ahypoglycemic compound, for example those as described in WO2008035305,WO2008035306, WO2008035686.

In one embodiment, the further active ingredient is an inductor oflipoic acid synthetase, for example those as described in WO2008036966,WO2008036967.

In one embodiment, the further active ingredient is a stimulator ofendothelial nitric oxide synthase (eNOS), for example those as describedin WO2008058641, WO2008074413.

In one embodiment, the further active ingredient is a modulator ofcarbohydrate and/or lipid metabolism, for example those as described inWO2008059023, WO2008059024, WO2008059025, WO2008059026.

In a further embodiment, the further active ingredient is an angiotensinII receptor antagonist, for example those as described in WO2008062905,WO2008067378, WO2008062905.

In one embodiment, the further active ingredient is an agonist of thesphingosine 1-phosphate receptor (SIP), for example those as describedin WO2008064315, WO2008074820, WO2008074821, WO2008135522, WO2009019167,WO2009043013, WO2009080663, WO2009085847, WO2009151529, WO2009151621,WO2009151626, WO2009154737.

In one embodiment, the further active ingredient is an agent whichretards gastric emptying, for example 4-hydroxyisoleucine(WO2008044770).

In one embodiment, the further active ingredient is atrytophan-5-hydroxylase inhibitor-1 (TPH1 inhibitor), which modulatesgastrointestinal motility, as described, for example, in WO2009014972.

In one embodiment, the further active ingredient is a muscle-relaxingsubstance, as described, for example, in WO2008090200.

In a further embodiment, the further active ingredient is an inhibitorof monoamine oxidase B (MAO-B), for example those as described inWO2008092091, WO2009066152.

In a further embodiment, the further active ingredient is an inhibitorof monoamine oxidase A (MAO-A), for example those as described inWO2009030968.

In another embodiment, the further active ingredient is an inhibitor ofthe binding of cholesterol and/or triglycerides to the SCP-2 protein(sterol carrier protein-2), for example those as described inUS2008194658.

In a further embodiment, the further active ingredient is a compoundwhich binds to the β-subunit of the trimeric GTP-binding protein, forexample those as described in WO2008126920.

In one embodiment, the further active ingredient is a urate anionexchanger inhibitor 1, as described, for example, in WO2009070740.

In one embodiment, the further active ingredient is a modulator of theATP transporter, as described, for example, in WO2009108657.

In another embodiment, the further active ingredient is lisofylline,which prevents autoimmune damage to insulin-producing cells.

In yet another embodiment, the further active ingredient is an extractfrom Bidens pilosa with the ingredient cytopiloyne as described inEP1955701.

In one embodiment, the further active ingredient is an inhibitor ofglucosylceramide synthase, as described, for example, in WO2008150486.

In a further embodiment of the invention, the further active ingredientis a glycosidase inhibitor, as described, for example, in WO2009117829,WO2009155753.

In another embodiment, the further active ingredient is an ingredientfrom the plant Hoodia Gordonii, as described in US2009042813, EP2044852.

In one embodiment, the further active ingredient is an antidiabetic, forexample D-tagatose.

In one embodiment, the further active ingredient is a zinc complex ofcurcumin, as described in WO2009079902.

In one embodiment, the further active ingredient is an inhibitor of the“cAMP response element binding protein” (CREB), as described inWO2009143391.

In another embodiment, the further active ingredient is an antagonist ofthe bradykinin B1 receptor, as described in WO2009124746.

In a further embodiment, the further active ingredient is a compoundwhich is capable of modulating diabetic peripheral neuropathy (DPN).Such modulators are, for example, FK-1706 or SB-509, or those asdescribed in WO1989005304, WO2009092129, WO2010002956.

In one embodiment, the further active ingredient is a compound which iscapable of modulating diabetic nephropathy. Such compounds aredescribed, for example, in WO2009089545, WO2009153261.

In one embodiment, the further active ingredient is an inhibitor (e.g.an anti-CD38 antibody) of CD38, as described in US2009196825.

In one embodiment, the further active ingredient is an inhibitor ofhuman fibroblast growth factor receptor 4 (FGFR4), as described, forexample, in WO2009046141.

In a further embodiment of the invention, the further active ingredientis a compound which protects the beta cell, for example14-alpha-lipolyl-andrographolide (AL-1).

In yet another embodiment of the invention, the further activeingredient is the INGAP (islet neogenesis associated protein) peptide, apeptide which reestablishes insulin production in patients with diabetesmellitus.

In one embodiment of the invention, the further active ingredient is amodulator of the CFTR (cystic fibrosis transmembrane conductanceregulator), as described, for example, in US2009246137, US2009264433,US2009264441, US2009264471, US2009264481, US2009264486, WO2010019239.

In one embodiment of the invention, the further active ingredient is acompound which stimulates/modulates insulin release, for example thoseas described in WO2009109258, WO2009132739, US2009281057, WO2009157418.

In one embodiment of the invention, the further active ingredient is anextract from Hippophae rhamnoides, as described, for example, inWO2009125071.

In one embodiment of the invention, the further active ingredient is anfrom Huanglian and Ku Ding Cha, as described, for example, inWO2009133458.

In another embodiment, the further active ingredient is a root extractfrom Cipadessa baccifera, as described in US2009238900.

In one embodiment of the invention, the further active ingredients areborapetoside A and/or borapetoside C, which can be isolated from theplant SDH-V, a species of Tinospora crispa, as described, for example,in US2010016213.

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®, Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isconsidered to be covered within the scope of protection conferred by thepresent invention.

Also suitable are the following active ingredients for combinationpreparations:

all antiepileptics specified in the Rote Liste 2010, chapter 15;

all antihypertensives specified in the Rote Liste 2010, chapter 17;

all hypotonics specified in the Rote Liste 2010, chapter 19;

all anticoagulants specified in the Rote Liste 2010, chapter 20;

all arteriosclerosis drugs specified in the Rote Liste 2010, chapter 25;

all beta receptors, calcium channel blockers and inhibitors of the reninangiotensin system specified in the Rote Liste 2010, chapter 27;

all diuretics and perfusion-promoting drugs specified in the Rote Liste2010, chapter 36 and 37;

all withdrawal drugs/drugs for the treatment of addictive disordersspecified in the Rote Liste 2010, chapter 39;

all coronary drugs and gastrointestinal drugs specified in the RoteListe 2010, chapter 55 and 60;

all migraine drugs, neuropathy preparations and Parkinson's drugsspecified in the Rote Liste 2010, chapter 61, 66 and 70.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isconsidered to be covered within the scope of protection conferred by thepresent invention.

The examples adduced hereinafter serve to illustrate the invention, butwithout restricting it.

TABLE 1 I

Ex. R1 R2 R6 R3 R4 R5 R7 R8 X A 1 —C≡C—CH₃ H H 3-C(CH₃)₃ H H H H —CH₂—phenyl 2 —C≡C—CH₃ H H 4-CF₃ H H H H —CH₂— phenyl 3 —C≡C—CH₃ H H 3-Cl H HH H —CH₂— phenyl 4 —C≡C—CH₃ H H 4-CF₃ 2-Cl H H H —OCH₂— phenyl 5—C≡C—CH₃ H H 3-C(CH₃)₃ H H H H —CH₂CH₂— phenyl 6 —C≡C—CH₃ H H 4-CF₃ H HH H —CH₂CH₂— phenyl 7 —C≡C—CH₃ H H 3-CH₃ H H H H —CH₂CH₂— phenyl 8—C≡C—CH₃ H H H H H H H —CH₂CH₂— phenyl 9 —C≡C—CH₃ H H 3-CF₃ 5-CF₃ H H H—CH₂— phenyl 10 —C≡C—CH₃ H H H H H H H —CH₂— phenyl 11 —C≡C—CH₃ H H3-CH₃ H H H H —CH₂— phenyl 12 —C≡C—CH₃ H H 3-Cl 4-CN H H H —CH₂— phenyl13 —C≡C—CH₃ H H 6-CF₃ H H H H —CH₂— 3-pyridyl 14 —C≡C—CH₃ H H 5-CF₃ H HH H —CH₂— 2-pyridyl 15 —C≡C—CH₃ H H 2-Cl 4-CF₃ H H H —CH₂— phenyl 16—OCH₃ H H 5-CF₃ H H H H —CH₂— 2-pyridyl 17 —OCH₃ H H 6-CF₃ H H H H —CH₂—3-pyridyl 18 —C≡C—CH₃ H H 2-CH₃ H H H H —CH₂— phenyl 19 —C≡C—CH₃ H H 4-FH H H H —CH₂— phenyl 20 —C≡C—CH₃ H H 3-F H H H H —CH₂— phenyl 21—C≡C—CH₃ H H 2-F H H H H —CH₂— phenyl 22 —C≡C—CH₃ H H 3-Cl 4-F H H H—CH₂— phenyl 23 —C≡C—CH₃ H H 2-CH₃ 4-F H H H —CH₂— phenyl 24 —C≡C—CH₃ HH 3-CH₃ 4-F H H H —CH₂— phenyl 25 —C≡C—CH₃ H H 2-Cl 4-F H H H —CH₂—phenyl 26 —C≡C—CH₃ H H 3-CF₃ H H H H —CH₂— phenyl 27 —C≡C—CH₃ H H H H HH H —CH₂— 2-pyridyl 28 —OCH₃ H H 3-Cl 5-Cl H H H —CH₂— 2-pyridyl 29—OCH₃ H H H H H H H —CH₂— phenyl 30 —OCH₃ H H 4-F H H H H —CH₂— phenyl31 —OCH₃ H H 3-F H H H H —CH₂— phenyl 32 —C≡C—CH₃ H H 3-Cl 5-Cl H H H—CH₂— 2-pyridyl

The efficacy of the compounds was tested as follows:

In Vitro FLIPR Assay with Recombinant Cells which Express the GPCR GPR40

Function-testing assays were performed by means of the FLIPR technique(“Fluorescence Imaging Plate Reader”, Molecular Devices Corp.). For thispurpose, agonist-induced changes were determined in the intracellularconcentration of Ca²⁺ in recombinant HEK293 cells which expressed theGPCR GPR40.

For the studies, cells were sown into 96-well microtiter plates (60 000cells/well) and left to grow overnight. The medium was removed and thecells were incubated in buffer which contains the fluorescent dyeFluo-4. After this loading with dye, the cells were washed, testsubstance was added and changes were measured in the intracellular Ca²⁺concentration in the FLIPR instrument. Results were presented as thepercentage change relative to the control (0%: no test substance added;100%: 10 μM reference agonist linoleic acid added) and used to calculatedose/effect curves, and EC₅₀ values were determined.

TABLE 2 Biological activity Ex. Rat EC₅₀ [μM] 1 0.73 2 0.37 3 0.29 42.55 5 2.56 6 1.32 7 1.54 8 0.45 9 1.66 10 0.07 11 0.15 12 0.14 13 0.7114 0.17 15 1.58 16 2.46 18 0.06 19 0.07 20 0.07 21 0.11 22 0.33

It can be seen from the table that the compounds of the formula Iactivate the GPR40 receptor and are thus very suitable for treatment ofhyperglycemia and of diabetes. The compounds of the formula I increaseinsulin excretion (see Itoh et al., Nature 2003, 422, 173-176).

Due to the activation of the GPR40 receptor, the compounds of theformula I can also be employed for treatment or prevention of furtherdisorders.

The compounds of the present invention are especially suitable fortreatment and/or prevention of:

-   1.    -   disorders of fatty acid metabolism and glucose utilization        disorders    -   disorders involving insulin resistance-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this context are        -   hyperglycemia,        -   improvement in insulin resistance,        -   improvement in glucose tolerance,        -   protection of the pancreatic β cells        -   prevention of macro- and microvascular disorders-   3. Various other conditions which may be associated with metabolic    syndrome or syndrome X, such as    -   increased abdominal girth    -   dyslipidemia (e.g. hypertriglyceridemia and/or low HDL)    -   insulin resistance    -   hypercoagulability    -   hyperuricemia    -   microalbuminemia    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure, for example (but not restricted to) following        myocardial infarction, hypertensive heart disease or        cardiomyopathy-   4. Memory disorders, cognitive defects, CNS disorders such as    -   age-related dementia    -   Alzheimer's disease    -   treatment of reduced attentiveness or wakefulness    -   schizophrenia        General Preparation Methods

The inventive compounds of the formula I can be prepared according tothe following reaction scheme:

Method A:

A spiro compound of the general formula A in which X, R7 and R8 are eachas defined above is reacted with a phenol of the general formula B inwhich R1, R2 and R6 are each as defined above and R is an alkyl groupsuch as methyl or ethyl, in the case that Y is a hydroxyl group underMitsunobu conditions, in the presence of, for example,triphenylphosphine and diethyl diazodicarboxylate, in an aproticsolvent, for example dichloromethane, to give the spirocyclicsubstituted 1,3-propane dioxide derivative of the general formula C. Inthe case that Y is a halide, for example bromide or a leaving group, forexample mesylate or tosylate, the conversion to the compound of thegeneral formula C takes place in a polar aprotic solvent, for exampledimethylformamide, in the presence of a base, for example cesiumcarbonate. The compound of the general formula C is either reacted underMitsunobu conditions, in the presence of, for example,triphenylphosphine and diethyl diazodicarboxylate, in an aproticsolvent, for example dichloromethane, with a compound of the generalformula D in which B, R3, R4 and R5 are each as defined above and FG isa hydroxyl group, or under the conditions of an aromatic nucleophilicsubstitution, in a polar aprotic solvent, for example dimethylformamide,in the presence of a base, for example sodium hydride, with a compoundof the general formula D in which B, R3, R4 and R5 are each as definedabove and FG is a fluorine or chlorine atom, to give the spirocyclicsubstituted 1,3-propane dioxide derivative of the general formula E. Thespirocyclically substituted 1,3-propane dioxide derivative of thegeneral formula E can alternatively also be obtained by first reactingthe Spiro compound of the general formula A in which X, R7 and R8 areeach as defined above, either under Mitsunobu conditions in the casethat Y is a hydroxyl group, in the presence of, for example,triphenylphosphine and diethyl diazodicarboxylate, in an aproticsolvent, for example dichloromethane, with a compound of the generalformula D in which B, R3, R4 and R5 are each as defined above and FG isa hydroxyl group, or under the conditions of an aromatic nucleophilicsubstitution, in the case that Y is a hydroxyl group in a polar aproticsolvent, for example dimethylformamide, in the presence of a base, forexample sodium hydride, with a compound of the general formula D inwhich B, R3, R4 and R5 are each as defined above and FG is a fluorine orchlorine atom, to give the spirocyclic substituted 1,3-propane dioxidederivative of the general formula F. In the case that Y is a halide, forexample bromide, or a leaving group, for example mesylate or tosylate,and FG is a hydroxyl group, the reaction to give the compound of thegeneral formula F takes place in a polar aprotic solvent, for exampledimethylforinamide, in the presence of a base, for example cesiumcarbonate. The compound of the general formula F is then reacted underMitsunobu conditions, in the presence of, for example,triphenylphosphine and diethyl diazodicarboxylate, in an aproticsolvent, for example dichloromethane, with a phenol of the generalformula B in which R1, R2 and R6 are each as defined above and R is analkyl group such as methyl or ethyl, to give the spirocyclic substituted1,3-propane dioxide derivative of the general formula E. Under theaction of a base, for example sodium hydroxide, in a solvent mixture,for example methanol, tetrahydrofuran and water, the ester of thegeneral formula E is cleaved to obtain the free carboxylic acid of thegeneral formula I. This method was used to prepare examples 1-32.

LIST OF ABBREVIATIONS

-   Ac acetyl-   Bn benzyl-   iBu isobutyl-   tBu tert-butyl-   BuLi n-butyllithium-   TLC thin-layer chromatography-   DEAD diethyl azodicarboxylate-   DCI direct chemical ionization (in MS)-   DCM dichloromethane-   DMAP 4-N,N-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EE ethyl acetate-   ent enantiomer/enantiomerically pure-   EI electron impact ionization (in MS)-   eq equivalent-   ESI electrospray ionization (in MS)-   FG functional group-   Hal halogen-   HPLC high-pressure, high-performance liquid chromatography-   LC-MS liquid chromatography-coupled mass spectrometry-   m meta-   Me methyl-   MeOH methanol-   MS mass spectrometry-   Ms mesyl-   NMR nuclear magnetic resonance spectroscopy-   o ortho-   p para-   Pd/C palladium on carbon-   iPr isopropyl-   nPr n-propyl-   rac racemic/racemic mixture-   Rf retention time (in TLC)-   RP reverse phase-   THF tetrahydrofuran-   Ts tosyl

EXPERIMENTAL Example Syntheses According to Method A Example 13-{4-[1-(3-tert-Butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

1-(3-tert-Butylphenoxymethyl)cyclopropyl]methanol

0.96 ml of 1,1-bis(hydroxymethylcyclopropane), 1.0 g of3-tert-butylphenol and 1.75 g of triphenylphosphine were dissolved in100 ml of dichloromethane. While cooling with ice, 0.88 ml of diethylazodicarboxylate was added dropwise. The ice bath was removed and thereaction mixture was stirred at room temperature for 4 hours. Then 5 mlof water were added cautiously and the reaction mixture was concentratedunder reduced pressure. The residue was taken up in 50 ml of water and50 ml of ethyl acetate. The organic phase was removed, dried over MgSO₄and then concentrated under reduced pressure. The residue was purifiedon silica gel with the n-heptane/ethyl acetate solvent mixture as alinear gradient of 100% n-heptane=>100% ethyl acetate. This gave 580 mgof 1-(3-tert-butylphenoxymethyl)cyclopropyl]methanol.

C₁₅H₂₂O₂ (234.34), LCMS (ESI-pos): 217.2 (M−H₂O+H⁺).

Methyl3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate

537 mg of 1-(3-tert-butylphenoxymethyl)cyclopropyl]methanol, 500 mg ofmethyl 3-(4-hydroxyphenyl)hex-4-ynoate and 600 mg of triphenylphosphinewere dissolved in 80 ml of dichloromethane. While cooling with ice, 0.31ml of diethyl azodicarboxylate were added dropwise. The ice bath wasremoved and the reaction mixture was stirred at room temperature for 24hours. Then 5 ml of water were added cautiously and the reaction mixturewas concentrated under reduced pressure. The residue was taken up in 50ml of water and 50 ml of ethyl acetate. The organic phase was removed,dried over MgSO₄ and then concentrated under reduced pressure. Theresidue was purified on silica gel with the n-heptane/ethyl acetatesolvent mixture as a linear gradient of 100% n-heptane=>100% ethylacetate. This gave 410 mg of methyl3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate.

C₂₈H₃₄O₄ (434.58), LCMS (ESI-pos): 435.3 (M+H⁺).

3-{4-[1-(3-tert-Butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

410 mg of methyl3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoatewere dissolved in a mixture of THF/MeOH/2N NaOH=1:1:1 (5 ml of each) andstirred at room temperature. After 45 min, the mixture was acidified topH 1 by adding 4N HCl. 50 ml of water were added, the mixture wasextracted three times with 50 ml each time of ethyl acetate. Thecombined organic phases were dried over MgSO₄ and then concentratedunder reduced pressure. The residue was purified by means of RP-HPLC.This gave 148 mg of3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₇H₃₂O₄ (420.55), LCMS (ESI-neg): 419.5 (M−H⁺).

Example 23-{4-[1-(4-Trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1, 1,1-bis(hydroxymethylcyclopropane),4-hydroxybenzotrifluoride and methyl 3-(4-hydroxyphenyl)hex-4-ynoatewere used to obtain3-{4-[1-(4-trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₃F₃O₄. (432.44), LCMS (ESI-neg): 431.4 (M−H⁺).

Example 33-{4-[1-(3-Chlorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1, 1,1-bis(hydroxymethylcyclopropane),3-chlorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain3-{4-[1-(3-chlorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₃ClO₄. (398.89), LCMS (ESI-neg): 397.4 (M−H⁺).

Example 43-{4-[3-(2-Chloro-4-trifluoromethylphenoxymethyl)oxetan-3-ylmethoxy]phenyl}hex-4-ynoicacid

[3-(2-Chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol

600 mg of 3-chloro-4-hydroxybenzotrifluoride and 829 mg of3-bromomethyl-3-oxetanemethanol were dissolved in 20 ml of acetonitrile,and 1.49 g of cesium carbonate were added. The reaction mixture washeated to 110° C. and stirred at this temperature for three hours. 50 mlof water and 50 ml of ethyl acetate were added to the cooled reactionmixture. The organic phase was removed, dried over MgSO₄ and thenconcentrated under reduced pressure. The residue was purified on silicagel with the n-heptane/ethyl acetate solvent mixture as a lineargradient of 100% n-heptane=>100% ethyl acetate. This gave 990 mg of[3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol.

C₁₂H₁₂ClF₃O₃. (296.68), LCMS (ESI-neg): 341.0 (M+HCOO⁻).

3-{4-[3-(2-Chloro-4-trifluoromethylphenoxymethyl)oxetan-3-ylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1,[3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]-methanol andmethyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-ylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₂ClF₃O₅. (482.89), LCMS (ESI-neg): 481.3 (M−H⁺).

Example 53-{4-[1-(3-tert-Butylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1, cyclobutane-1,1-diyldimethanol,3-tert-butylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were usedto obtain3-{4-[1-(3-tert-butylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoicacid.

C₂₈H₃₄O₄. (434.58), LCMS (ESI-neg): 433.4 (M−H⁺).

Example 63-{4-[1-(4-Trifluoromethylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1, cyclobutane-1,1-diyldimethanol,4-hydroxybenzotrifluoride and methyl 3-(4-hydroxyphenyl)hex-4-ynoatewere used to obtain3-{4-[1-(4-trifluoromethylphenoxymethyl)cyclobutylmethoxy]phenyl}hex-4-ynoicacid.

C₂₅H₂₅F₃O₄. (446.47), LCMS (ESI-neg): 445.3 (M−H⁺).

Example 7 3-[4-(1-m-Tolyloxymethylcyclobutylmethoxy)phenyl]hex-4-ynoicacid

Analogously to example 1, cyclobutane-1,1-diyldimethanol, 3-methylphenoland methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-[4-(1-m-tolyloxymethylcyclobutylmethoxy)phenyl]hex-4-ynoic acid.

C₂₅H₂₈O₄. (392.49), LCMS (ESI-neg): 391.3 (M−H⁺).

Example 8 3-[4-(1-Phenoxymethylcyclobutylmethoxy)phenyl]hex-4-ynoic acid

Analogously to example 1, cyclobutane-1,1-diyldimethanol, phenol andmethyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-[4-(1-phenoxymethylcyclobutylmethoxy)phenyl]hex-4-ynoic acid.

C₂₄H₂₆O₄. (378.47), LCMS (ESI-neg): 377.3 (M−H⁺).

Example 93-{4-[1-(3,5-Bis(trifluoromethyl)phenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1, 1,1-bis(hydroxymethylcyclopropane),3,5-bis(trifluoromethyl)phenol and methyl3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(3,5-bis(trifluoromethyl)phenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₅H₂₂F₆O₄. (500.44), LCMS (ESI-neg): 499.4 (M−H⁺).

Example 10 3-[4-(1-Phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoicacid

Methyl 3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate

300 mg of methyl 3-(4-hydroxyphenyl)hex-4-ynoate were dissolved in 10 mlof DCM and used to charge a microwave vessel, then 234 mg of1,1-bis(hydroxymethylcyclopropane) and 541 mg of triphenylphosphine(polymer-bound, Reagentplus 99%) were added, and the mixture was stirredfor 10 min to swell the resin. Subsequently, 0.41 ml of diisopropylazodicarboxylate was added and the mixture was stirred at 120° C. undermicrowave irradiation for 15 min. The cooled reaction mixture wasfiltered and the filtercake was washed 3× with 10 ml each time of DCM.The combined filtrates were washed with 30 ml of water, then dried usinga ChemElut cartridge and concentrated under reduced pressure. Theresidue was purified by means of RP-HPLC. This gave 200 mg of methyl3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate.

C₁₈H₂₂O₄. (302.37), LCMS (ESI-pos): 285.1 (M−H₂O+H⁺).

Methyl 3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]-hex-4-ynoate

100 mg of methyl3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate weredissolved in 10 ml of DCM and used to charge a microwave vessel, then46.7 mg of phenol and 130 mg of triphenylphosphine (polymer-bound,Reagentplus 99%) were added, and the mixture was stirred for 10 min toswell the resin. Subsequently, 98 μl of diisopropyl azodicarboxylatewere added and the mixture was stirred at 120° C. under microwaveirradiation for 15 min. The cooled reaction mixture was filtered and thefiltercake was washed 3× with 10 ml each time of DCM. The combinedfiltrates were washed with 30 ml of water, then dried using a ChemElutcartridge and concentrated under reduced pressure. The residue waspurified by means of RP-HPLC. This gave 68 mg of methyl3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate.

C₂₄H₂₆O₄. (378.47), LCMS (ESI-pos): 396.2 (M+NH₄ ⁺).

3-[4-(1-Phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoic acid

Analogously to example 1, methyl3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate was used toobtain 3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]hex-4-ynoic acid.

C₂₃H₂₄O₄. (364.44), LCMS (ESI-neg): 363.3 (M−H⁺).

Example 11 3-[4-(1-m-Tolyloxymethylcyclopropylmethoxy)phenyl]hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3-methylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain 3-[4-(1-m-tolyloxymethylcyclopropylmethoxy)phenyl]hex-4-ynoicacid.

C₂₄H₂₆O₄. (378.47), LCMS (ESI-neg): 377.3 (M−H⁺).

Example 123-{4-[1-(3-Chloro-4-cyanophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

2-Chloro-4-(1-hydroxymethylcyclopropylmethoxy)benzonitrile

15.0 g of 1,1-bis(hydroxymethylcyclopropane) and 7.4 g of2-chloro-4-fluorobenzonitrile were dissolved in 350 ml ofN-methylpyrrolidone, and 1.26 g of NaH were introduced in portions whilecooling with ice. After 30 minutes, the cooling bath was removed and thereaction mixture was stirred at room temperature for 2 hours. Then thereaction mixture was quenched by cautiously adding 250 ml of water, andit was extracted three times with portions each of 200 ml of ethylacetate. The combined organic phases were dried over MgSO₄ and thenconcentrated under reduced pressure. The residue was purified on silicagel with the n-heptane/ethyl acetate solvent mixture as a lineargradient of 100% n-heptane=>50% n-heptane+50% ethyl acetate. This gave10.5 g of 2-chloro-4-(1-hydroxymethylcyclopropylmethoxy)benzonitrile.

C₁₂H₁₂ClNO₂ (237.69), LCMS (ESI-pos): 238.0 (M+H⁺); TLC inEA:n-heptane=1:1; R_(f)=0.29.

3-{4-[1-(3-Chloro-4-cyanophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 1,2-chloro-4-(1-hydroxymethylcyclopropylmethoxy)benzonitrile and methyl3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(3-chloro-4-cyanophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₂ClNO₄. (423.90), LCMS (ESI-neg): 422.3 (M−H⁺).

Example 133-{4-[1-(6-Trifluoromethylpyridin-3-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 12 and example 1,1,1-bis(hydroxymethylcyclopropane), 5-fluoro-2-(trifluoromethyl)pyridineand methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(6-trifluoromethylpyridin-3-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₂F₃NO₄. (433.43), LCMS (ESI-neg): 432.4 (M−H⁺).

Example 143-{4-[1-(5-Trifluoromethylpyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 12 and example 1,1,1-bis(hydroxymethylcyclopropane), 2-fluoro-5-(trifluoromethyl)pyridineand methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(5-trifluoromethylpyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₂F₃NO₄. (433.43), LCMS (ESI-neg): 432.4 (M−H⁺).

Example 153-{4-[1-(2-Chloro-4-trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-acid

Analogously to example 12 and example 1,1,1-bis(hydroxymethylcyclopropane), 3-chloro-4-fluorobenzotrifluorideand methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(2-chloro-4-trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₂ClF₃O₄. (466.89), LCMS (ESI-neg): 465.2 (M−H⁺).

Example 163-Methoxy-3-{4-[1-(5-trifluoromethylpyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}-propionicacid

Ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate

23.8 ml of diisopropylamine were initially charged under argon in 250 mlof THF and cooled to 0° C., and 70 ml of n-butyllithium solution (2.5 Min toluene) were added. The mixture was stirred at 0° C. for 30 minutes,then cooled to −75° C., 16.2 ml of ethyl acetate were added slowly andthe mixture was stirred for 30 minutes. Then, at −75° C., 30 g ofp-benzyloxybenzaldehyde, dissolved in 250 ml of THF, were added dropwise(internal temp. max. −68° C.; 1 h). The mixture was stirred for afurther 20 minutes and then the reaction mixture was quenched with 200ml of sat. NH₄Cl solution and 20 ml of 1 N HCl (internal temp. max. −50°C.). The mixture was allowed to thaw to room temperature, the phaseswere separated and the organic phase was washed three times with 100 mleach time of sat. NH₄Cl solution and once with 100 ml of sat. NaClsolution. The solvent was removed under reduced pressure. The residuewas extracted by stirring with n-heptane/2% THF and the precipitatedsolid was filtered off with suction and dried under reduced pressure at40° C. This gave 41 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionateas a colorless solid.

C₁₈H₂₀O₄ (300.36), LCMS (ESI-pos): 283.1 (M−H₂O+H⁺).

Ethyl 3-(4-benzyloxyphenyl)-3-methoxypropionate

40 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate, 75 g of silveroxide and 83 ml of iodomethane were initially charged in 350 ml oftoluene and stirred in a closed vessel at bath temperature 70° C. for 24hours. Then a further 20 ml of iodomethane were added and the mixturewas stirred at bath temperature 70° C. for a further 48 hours. Thereaction mixture was filtered through a short silica gel layer andwashed with toluene, and then the toluene was removed under reducedpressure. The residue was purified on silica gel with the eluent ethylacetate:n-heptane=1:2. This gave 22.9 g of ethyl3-(4-benzyloxyphenyl)-3-methoxypropionate.

C₁₉H₂₂O₄ (314.38), LCMS (ESI-pos): 283.1 (M−CH₃OH+H⁺).

Ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate

9.3 g of ethyl 3-(4-benzyloxyphenyl)-3-methoxypropionate were dissolvedin 200 ml of ethanol, and 1.1 g of palladium on activated carbon (10%)were added. The mixture was stirred under a hydrogen atmosphere at roomtemperature for two hours. The reaction mixture was filtered through anylon membrane filter (0.45 μm) and washed with 200 ml of ethanol, andthe filtrate was concentrated under reduced pressure. This gave 6.7 g ofethyl 3-(4-hydroxyphenyl)-3-methoxypropionate.

C₁₂H₁₆O₄ (224.26), LCMS (ESI-pos): 193.1 (M−CH₃OH+H⁺). ¹H NMR (500 MHz,DMSO-d₆) δ 9.39 (s, 1H), 7.12 (d, 2H), 6.73 (d, 2H), 4.44 (dd, 1H), 4.02(q, 2H), 3.03 (s, 3H), 2.68 (dd, 2H), 2.53 (dd, 2H), 1.14 (t, 3H).

3-Methoxy-3-{4-[1-(5-trifluoromethylpyridin-2-oxymethyl)cyclopropylmethoxy]phenyl}propionicacid

Analogously to example 12 and example 1,1,1-bis(hydroxymethylcyclopropane), 2-fluoro-5-(trifluoromethyl)pyridineand ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate were used to obtain3-methoxy-3-{4-[1-(5-trifluoromethylpyridin-2-yloxymethyl)cyclopropylmethoxy]-phenyl}propionicacid.

C₂₁H₂₂F₃NO₅. (425.41), LCMS (ESI-neg): 424.3 (M−H⁺).

Example 173-Methoxy-3-{4-[1-(6-trifluoromethylpyridin-3-yloxymethyl)cyclopropylmethoxy]phenyl}-propionicacid

Analogously to example 16 and example 1,1,1-bis(hydroxymethylcyclopropane), 5-fluoro-2-(trifluoromethyl)pyridineand ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate were used to obtain3-methoxy-3-{4-[1-(6-trifluoromethylpyridin-3-yloxymethyl)cyclopropylmethoxy]-phenyl}propionicacid.

C₂₁H₂₂F₃NO₅. (425.41), LCMS (ESI-neg): 424.4 (M−H⁺).

Example 18 3-[4-(1-o-Tolyloxymethylcyclopropylmethoxy)phenyl]hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),2-methylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain 3-[4-(1-o-tolyloxymethylcyclopropylmethoxy)phenyl]hex-4-ynoicacid.

C₂₄H₂₆O₄. (378.47), LCMS (ESI-neg): 377.3 (M−H⁺).

Example 193-{4-[1-(4-Fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),4-fluorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain3-{4-[1-(4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₃FO₄. (382.44), LCMS (ESI-neg): 381.3 (M−H⁺).

Example 203-{4-[1-(3-Fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3-fluorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain3-{4-[1-(3-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₃FO₄. (382.44), LCMS (ESI-neg): 381.2 (M−H⁺).

Example 213-{4-[1-(2-Fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),2-fluorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used toobtain3-{4-[1-(2-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₃FO₄. (382.44), LCMS (ESI-neg): 381.2 (M−H⁺).

Example 223-{4-[1-(3-Chloro-4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3-chloro-4-fluorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate wereused to obtain3-{4-[1-(3-chloro-4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₂ClFO₄. (416.88), LCMS (ESI-neg): 415.3 (M−H⁺).

Example 233-{4-[1-(4-Fluoro-2-methylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),4-fluoro-2-methylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate wereused to obtain3-{4-[1-(4-fluoro-2-methylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₅FO₄. (396.46), LCMS (ESI-neg): 395.4 (M−H⁺).

Example 243-{4-[1-(4-Fluoro-3-methylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),4-fluoro-3-methylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate wereused to obtain3-{4-[1-(4-fluoro-3-methylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₅FO₄. (396.46), LCMS (ESI-neg): 395.3 (M−H⁺).

Example 253-{4-[1-(2-Chloro-4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),2-chloro-4-fluorophenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate wereused to obtain3-{4-[1-(2-chloro-4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₃H₂₂ClFO₄. (416.88), LCMS (ESI-neg): 415.2 (M−H).

Example 263-{4-[1-(3-Trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3-trifluoromethylphenol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate wereused to obtain3-{4-[1-(3-trifluoromethylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₄H₂₃F₃O₄. (432.44), LCMS (ESI-neg): 431.4 (M−H).

Example 273-{4-[1-(Pyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),2-hydroxypyridine and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were usedto obtain3-{4-[1-(pyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₂H₂₃NO₄. (365.43), LCMS (ESI-pos): 366.3 (M+H⁺).

Example 283-{4-[1-(3,5-Dichloropyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid

Analogously to example 16, 1,1-bis(hydroxymethylcyclopropane),3,5-dichloro-2-fluoropyridine and ethyl3-(4-hydroxyphenyl)-3-methoxypropionate were used to obtain3-{4-[1-(3,5-dichloropyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid.

C₂₀H₂₁Cl₂NO₅. (426.30), LCMS (ESI-pos): 426.2 (M+H⁺).

Example 293-Methoxy-3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]propionic acid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane), phenoland ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate were used to obtain3-methoxy-3-[4-(1-phenoxymethylcyclopropylmethoxy)phenyl]propionic acid.

C₂₁H₂₄O₅. (356.42), LCMS (ESI-neg): 355.3 (M−H⁺).

Example 303-{4-[1-(4-Fluorophenoxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),4-fluorophenol and ethyl were used to obtain3-{4-[1-(4-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid.

C₂₁H₂₃FO₅. (374.41), LCMS (ESI-neg): 373.3 (M−H⁺).

Example 313-{4-[1-(3-Fluorophenoxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3-fluorophenol and ethyl 3-(4-hydroxyphenyl)-3-methoxypropionate wereused to obtain3-{4-[1-(3-fluorophenoxymethyl)cyclopropylmethoxy]phenyl}-3-methoxypropionicacid.

C₂₁H₂₃FO₅. (374.41), LCMS (ESI-neg): 373.2 (M−H⁺).

Example 323-{4-[1-(3,5-Dichloropyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid

Analogously to example 10, 1,1-bis(hydroxymethylcyclopropane),3,5-dichloro-2-hydroxypyridine and methyl3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain3-{4-[1-(3,5-dichloropyridin-2-yloxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoicacid.

C₂₂H₂₁Cl₂NO₄. (434.32), LCMS (ESI-pos): 434.3, 436.2 (M+H⁺).

The invention claimed is:
 1. A compound of the formula I

in which R1 is (C₂-C₆)-alkynyl; R2, R6 are H; R3, R4 are eachindependently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃, or (C₁-C₆)-alkyl; R5is H; R7, R8 are H; A is phenyl, or pyridyl; and X is —CH₂—, or—CH₂—CH₂—; or a physiologically compatible salt thereof.
 2. The compoundas claimed in claim 1, wherein R1 is (C₂-C₆)-alkynyl; R2, R6 are H; R3,R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃, OCF₃, or(C₁-C₆)-alkyl; R5 is H; R7, R8 are H; A is phenyl; and X is —CH₂—, or—CH₂—CH₂—; or a physiologically compatible salts thereof.
 3. Thecompound as claimed in claim 1, wherein R1 is (C₂-C₆)-alkynyl; R2, R6are H; R3, R4 are each independently H, F, Cl, Br, I, CF₃, CN, CF₃,OCF₃, or (C₁-C₆)-alkyl; R5 is H; R7, R8 are H; A is pyridyl; and X is—CH₂—, or —CH₂—CH₂—; or a physiologically compatible salt thereof. 4.The compound as claimed in claim 1, wherein R1 is O—(C₁-C₆)-alkyl, or(C₂-C₆)-alkynyl; R2, R6 are H; R3, R4 are each independently H, F, Cl,Br, I, CF₃, CN, CF₃, OCF₃, or (C₁-C₆)-alkyl; R5 is H; R7, R8 are H; A isphenyl, 2-pyridyl, or 3-pyridyl; and X is —CH₂—, or —CH₂—CH₂—; or aphysiologically compatible salt thereof.
 5. A pharmaceutical compositioncomprising one or more compounds as claimed in claim
 1. 6. Thepharmaceutical composition as claimed in claim 5, which comprises afurther active ingredient selected from one or more antidiabetics,active hypoglycemic ingredients, HMG-CoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha/gamma agonists, PPAR delta agonists, fibrates, MTPinhibitors, bile acid absorption inhibitors, CETP inhibitors, polymericbile acid adsorbers, LDL receptor inducers, ACAT inhibitors,antioxidants, lipoprotein lipase modulators, ATP citrate lyaseinhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists,HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, glycogen phosphorylase inhibitors, glucagon receptorantagonists, activators of glucokinase, inhibitors of gluconeogenesis,inhibitors of fructose 1,6-biphosphatase, modulators of glucosetransporter 4, inhibitors of glutamine:fructose-6-phosphateamidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoAcarboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitorsof glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta,endothelin-A receptor antagonists, inhibitors of I kappaB kinase,modulators of the glucocorticoid receptor, CART modulators, NPYagonists, MC4 agonists, orexin receptor 1 antagonists, orexin receptor 2antagonists, H3 agonists, TNF agonists, CRF antagonists, CRF BPantagonists, urocortin agonists, β3 agonists, CB 1 receptor antagonists,MSH (melanocyte-stimulating hormone) agonists, CCK-A modulators,serotonin reuptake inhibitors, mixed serotoninergic and noradrenergiccompounds, 5HT agonists, bombesin agonists, galanin antagonists, growthhormones, growth hormone-releasing compounds, TRH agonists, decouplingprotein 2 or 3 modulators, leptin agonists, DA agonists, lipase/amylaseinhibitors, PPAR modulators, RXR modulators or TR-β-agonists oramphetamines.
 7. The pharmaceutical composition as claimed in claim 5,which comprises, as a further active ingredient selected from metformin,arcabose, glibenclamide, glimepiride, gliclazide, gliquidone,pioglitazone, rosiglitazone, exenatide, miglitol, vildagliptin,sitagliptin, repaglinide, nateglinide or mitiglinide.
 8. Thepharmaceutical composition as claimed in claim 5, which comprises, as afurther active ingredient, lixisenatide.
 9. A method for lowering bloodglucose in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition of claim
 5. 10. A method for treating diabetes in a patientin need thereof comprising administering to said patient atherapeutically effective amount of the pharmaceutical composition ofclaim
 5. 11. A method for increasing insulin excretion in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of the pharmaceutical composition of claim
 5. 12. A kitcomposed of separate packages of a) an effective amount of a compound offormula I as claimed in claim 1 and b) an effective amount of a furthermedicinal active ingredient.